Methods and compositions for treating tumours

Abstract

The invention relates to methods for treating tumours, methods for suppressing growth and / or inducing apoptosis in a tumour, methods for preparing combinatorial treatments and determining treatment regimens, and compositions and combinations suitable for use in the treatment of tumours.

Description

[0001] METHODS AND COMPOSITIONS FOR TREATING TUMOURS FIELD OF THE INVENTION The invention relates to methods for treating tumours, methods for suppressing growth and / or inducing apoptosis in a tumour, methods for preparing combinatorial treatments and determining treatment regimens, and compositions and combinations suitable for use in the treatment of tumours (both benign and malignant). The approaches described involve targeting multiple pathogenic genomic sequence variants using a combination of nucleic acid molecules, each targeting a particular variant or cluster of variants. BACKGROUND In the treatment of cancer, genetic or pathway-targeted therapies have been shown to improve patient response, however the development of resistance and the emergence of genetic subclones are ongoing challenges. Cancer is at its root a genetic disease, caused by multiple DNA variants / mutations emerging serially or in parallel in clones or subclones(3, 4). These pathogenic genetic variants lead to protection from normal homeostatic mechanisms including apoptosis(5-8). Genes which have been found recurrently to contain or be affected by pathogenic DNA sequence variants (also known as mutations) in the context of cancer have traditionally been termed oncogenes or tumour suppressor genes, which means that in their normal unmutated state they have the potential to promote or inhibit cancer growth respectively. However it has since been understood that in different situations the same gene may function as either an oncogene or a tumour suppressor, and in the cancer state the mutations in classical oncogenes and in classical tumour suppressors have the same effect, i.e. to promote cancer. All genes recurrently mutated in cancer can therefore be considered more broadly to be “oncogenes” and their mutations can be considered to be oncogenic mutations. In addition there are many genes associated with cancer, which can in some circumstances be considered to be oncogenes, but which are not recurrently mutated at DNA sequence level. Unless indicated otherwise, concerned here are genes which are recurrently mutated at DNA sequence level in cancer. Approaches exist in the art in which a single gene or multiple genes associated with cancer is targeted using an siRNA to inhibit overall expression of that gene. Such approaches can lead to unwanted off- target effects due to inhibition of expression in non-cancer cells as well as cancer cells. Alternatively, approaches exist in which a variant of a single gene that is associated with cancer is targeted using an siRNA to inhibit the expression of a variant allele specifically. Other approaches in the art target cancer or tumour-related genes with siRNA to inhibit overall expression of that gene in addition to targeting an oncogenic variant with an siRNA. However such targeting approaches do not target multiple oncogenic mutations, to inhibit the expression of multiple oncogenic variant alleles simultaneously.. Such approaches also do not tackle the genetic heterogeneity that is present in tumours arising from the different combinations of mutations present in genetic subclones. Existing chemotherapeutic, surgical and immunotherapeutic methods for treating cancer are not effective in all cancer types or for all subjects with a particular cancer type, and may benefit from additional, complementary therapeutic approaches being used in combination or alone, in particular those that target the underlying genetic cause of disease. Accordingly, there is a need in the art for approaches which trigger apoptosis in tumour cells, target the heterogeneous genetic nature of tumours, avoid the emergence of genetic subclones following treatment, and minimise unwanted side-effects. SUMMARY OF THE INVENTION In a first aspect, the invention provides a method of preparing a combinatorial treatment suitable for suppressing growth and / or inducing apoptosis in a tumour of a subject, the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; and b) providing a first nucleic acid molecule complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); thereby providing the combinatorial treatment. In a second aspect, the invention provides a method of preparing a combinatorial treatment suitable for treating a tumour in a subject, the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; and b) providing a first nucleic acid molecule complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); thereby providing the combinatorial treatment. In a third aspect, the invention provides a method of determining a treatment regimen suitable for suppressing growth and / or inducing apoptosis in a tumour in a subject; the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; and b) providing a first nucleic acid molecule complementary to an mRNA encoding a first pathogenic genomic sequence variant relevant to the tumour of the subject identified in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); thereby providing the treatment regimen. In a fourth aspect, the invention provides a method of determining a treatment regimen for treating a tumour in a subject; the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; and b) providing a first nucleic acid molecule complementary to an mRNA encoding a first pathogenic genomic sequence variant relevant to the tumour of the subject identified in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); thereby providing the treatment regimen. In a fifth aspect, the invention provides a method of suppressing growth and / or inducing apoptosis in a tumour of a subject, the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; b) providing a first nucleic acid molecule complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); and administering the first and second nucleic acid molecules to the subject. In a sixth aspect, the invention provides a method of treating a tumour in a subject, the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; b) providing a first nucleic acid molecule complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); and administering the first and second nucleic acid molecules to the subject. In a seventh aspect, the invention provides a composition comprising at least two nucleic acid molecules, wherein the composition is suitable for inducing apoptosis in a tumour in a subject, wherein a first nucleic acid molecule comprises a sequence that is complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject, and each further nucleic acid molecule comprises a sequence that is complementary to an mRNA of a different pathogenic genomic sequence variant relevant to the tumour of the subject. In an eighth aspect, the invention provides a combination comprising at least two nucleic acid molecules, wherein the combination is suitable for inducing apoptosis in a tumour in a subject; wherein a first nucleic acid molecule comprises a sequence that is complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject, and each further nucleic acid molecule comprises a sequence that is complementary to an mRNA of a different pathogenic genomic sequence variant relevant to the tumour of the subject. In a ninth aspect, the invention provides a composition or combination as described herein for use in a method of inducing apoptosis in a tumour of a subject. In a tenth aspect, the invention provides a composition or combination as described herein for use in a method of suppressing growth of a tumour of a subject. In an eleventh aspect, the invention provides a composition or combination as described herein for use in a method of treating cancer in a subject. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: The effects of siKRASG12V on confluency and apoptosis in HUVEC wild-type and mutant clones. (A)(B) Confluency and caspase 3 / 7 activity in HUVEC WT, B1 and C1 at 5 days. Unpaired t- test between scrambled control and siKRASG12V-treated cells. (C) Normalised confluency in WT, B1 and C1 over 5 days treated with Kras. Normalised to non-treated. Unpaired t-test between WT* and C1* at 5 days. (D) Caspase 3 / 7 activity over 5 days in WT, B1 and C1 treated with siKRASG12V. (E) Normalised confluency and caspase 3 / 7 activity at 5 days in WT, B1 and C1 treated with siKRASG12V. (F) Caspase 3 / 7 activity at 7 days between WT* and C1* treated with scrambled and siKRASG12V for 7 days. Figure 2: The proliferative and apoptotic effects of siNRAS treatment in a patient primary CMN cell line. a) Proliferation (left) and apoptosis (right) were measured over 5 days after a primary CMN cell line was treated with 25nM siNRAS specifically against the NRASc.181C>A p.Q61Kmutation harboured by this cell line. An extremely significant difference was measured between treatment with non-targeting siRNA and the targeted siRNA against NRASc.181C>A p.Q61K(p<0.0001) in both proliferation and apoptosis after 5 days. The statistical test used was an unpaired parametric t-test. Significance defined at p<0.05. Figure 3: Table showing pathogenic sequence variants detected in various cancer cell lines. Figure 4: RT-qPCR data of RNA levels following siRNA knockdown of hotspot mutations in SKOV3 cell line. A) RNA expression of wildtype PIK3CA and PIK3CA c.3140A>G. B) RNA expression of WT FBXW7 and FBXW7 c.1514G>T C) RNA expression of WT APC and APC c.4666delA. All data normalised to GAPDH expression. Statistical differences between siCTRL and designed siRNA examined by unpaired t-test *p<0.05, **p<0.001, ***p<0.0001. Figure 5: RT-qPCR data of RNA levels following siRNA knockdown of hotspot mutations in MCF-7 cell line. A) RNA expression of wildtype PIK3CA and PIK3CA c.1633G>A. B) RNA expression of WT GATA3 and GATA31006dupG. All data normalised to GAPDH expression. Statistical differences between siCTRL and designed siRNA examined by unpaired t-test *p<0.05, **p<0.001, ***p<0.0001. Figure 6: RT-qPCR data of RNA levels comparing single siRNA knockdown with siRNA MaGiC combination knockdown in SKOV3 cell line. A) Knockdown of single siRNA transfections for each oncogenic variant. B) Gene knockdown of WT and variant alleles when transfected with MaGiC siRNA combination (siPIK3CA+siFBXW7+siAPC) at 0 hours. C) Gene knockdown of WT and mutant alleles with repeated transfection with MaGiC siRNA combination (siPIK3CA+siFBXW7+siAPC) at 0 hours and 24 hours. Figure 7: RT-qPCR data of RNA levels comparing single siRNA knockdown with siRNA MaGiC combination knockdown in H1299 cell line. A) Knockdown of single siRNA transfections for each hot- spot gene mutation. B) Gene knockdown of WT and mutant alleles when transfected with MaGiC siRNA combination (siNRAS+siMYC) at 0 hours. C) Gene knockdown of WT and mutant alleles with repeated transfected with MaGiC siRNA combination (siNRAS+siMYC) at 0 hours and 24 hours. Figure 8: Variant specific BRAFV600E knockdown. Rt-qPCR data of RNA levels 48 hours after transfection with siRNA. Statistical differences between siCTRL and designed siRNA examined by unpaired t-test *p<0.05, **p<0.001, ***p<0.0001. Figure 9: Non-specific BRAFV600E knockdown. Rt-qPCR data of RNA levels 48 hours after transfection with siRNA. Statistical differences between siCTRL and designed siRNA examined by unpaired t-test *p<0.05, **p<0.001, ***p<0.0001. Figure 10: The effects between single siRNA vs double siRNA treatment in 3 carcinoma cell lines: SK-OV-3, MCF-7 and H1299. a) Proliferation (left) and apoptosis (right) in SK-OV-3 when treated with siRNA against PIK3CA (1), FBXW7 and a combination of both. Significance (p<0.0001) between non- targeting siRNA and double siRNA cocktail. b) Proliferation and apoptosis in MCF-7 when treated with siRNA against PIK3CA (2), GATA3 and a combination of both. Significance (p<0.0001) between non- targeting siRNA and siPIK3CA (2) and between siPIK3CA (2) and the combined siRNA cocktail. Notably, there was a highly statistical difference between single siGATA3 treatment and the siRNA combination. c) Proliferation and apoptosis in H1299 when treated with siNon-target, siNRAS, siMYC and a combination of siRNA against NRAS and MYC. Significance difference (p<0.0003) between non-targeting siRNA and double siRNA cocktail. There was no statistical difference between the single siRNAs and the combination siRNAs. Repeated measures two-way ANOVA performed for each statistical test. Significance defined at p<0.05. Figure 11: Treatment of ovarian cancer line SKOV3 with siRNAs targeted at the two highest allele load DNA variants resulted in suppression of proliferation and induction of apoptosis (circles), and this was more effective than either scrambled control (no significant effect) or treatment with a double target MaGiC (“MaGiC2”) therapy designed for a breast cancer line (down triangles). The difference between the two siRNA combinations was statistically significant (p<0.0001) in both confluency and caspase measures at 72 hours. The statistical t-test used was a parametric unpaired t-test. Significance defined at p<0.05. Figure 12: A comparison of cell proliferation and apoptosis between double (“MaGiC2”) and triple (“MaGiC3”) targeted siRNA in SK-OV-3. a) Both well confluency and apoptosis were imaged over 5 days in SK-OV-3 under double siRNA or triple siRNA treatment. Double siRNA treatment combined two concentrations of 18.75nM. In the triple combination, siRNA concentration was 12.5nM each. A significant difference was found between the double and triple combination (p=0.0007) in terms of caspase activity. Repeated measures two-way ANOVA, significance at p<0.05. Figure 13: A single dose of variant allele specific siRNA against NRAS c.181C>A, p.(Q61K) in patient naevus cells induces apoptosis synergistically with MEKi Trametinib. Figure 14: Allele-preferential siRNA KD of a single oncogene induces apoptosis across cell lines in culture. Example of testing of multiple siRNAs for allele-specificity - variant specific BRAFV600E knockdown. A) walk design of siRNA around the variant of interest. B) BRAFV600E and BRAF WT primer specificity test. RT-qPCR results showing variant allele expression in HERMES-1WT / WT and SKMEL-28V600E / V600E relative to expression of GAPDH. Raw Ct values of serial dilutions of cDNA indicate efficiency of primer binding. C) RNA expression of BRAFWT and BRAFV600E in heterozygous A2058s, 48 hours after transfection with siRNA (37.5nM). Statistical differences between siCTRL and BRAF-targeting siRNA examined by unpaired two-tailed t-test *p<0.05, **p<0.001, ***p<0.0001. Figure 15: Allele-preferential siRNA KD of a single oncogene induces apoptosis across cell lines in culture. Effect of single dose of siBRAFV600Eon cell viability of two BRAFV600Emelanoma cell linesA2058WT / V600E and SKMEL-28V600E / V600E in vitro. Cell viability assays were performed using the IncucyteLive Cell Imaging System. A,B) Proliferation analysis was determined by percentage confluency. C,D) Apoptosis analysis determined by Caspase 3 / 7 activity. siRNA transfected at concentration of 37.5nM. Data shown as mean ± SD of triplicate wells. Assays were run in parallel on the same wells. Statistical differences between siCTRL and siBRAFV600E were examined using two-way-ANOVA, *p<0.05, ** p<0.01, ***p<0.001. Figure 16: Allele-preferential siRNA KD of a single oncogene induces apoptosis across cell lines in culture. Dose dependent effects of siBRAFV600E on cell viability in A2058 melanoma cell line in vitro. A) Confluency and B) caspase 3 / 7 activity were quantified 3 days post transfection. Cells were treated with a 3-fold serial dilution of siRNA with a concentration range of 50nM-0.002nM. The dilution and dispersion of siRNA was automating using the Echo550 liquid handler. Data is fitted to a sigmoidal (four-parameter logistic) dose-response curve; error bars ± SD, n=3. Comparison of Fits siBRAFV600E and siCTRL p<0.0001. Figure 17: Addition of an additional “redundant” siRNA does not reduce efficacy of BRAFV600E- targeting siRNA. A) variant specific BRAFV600E knockdown in A2058V600E / WT. Knockdown levels consistent when transfected alone (siBRAF V600E) or in combination with siNRASc.181C>A p.Q61Kand siNRASc.182A>G p.Q61R(siCOMBO).. Rt-qPCR data of RNA levels 48 hours after transfection with siRNA. Statistical differences between siCTRL and designed siRNA examined by unpaired two-tailed t-test *p<0.05, **p<0.001, ***p<0.0001, n=3. B) Effect of siBRAF V600E vs siCOMBO on induction of apoptosis in A2058 cells. Statistical differences between siCTRL and siBRAFV600E were examined using repeated measures two-way-ANOVA ***p<0.001, n=5. Figure 18: Addition of “redundant” siRNA does not reduce efficacy of variant-targeting siRNA, where redundant means a variant allele specific siRNA being applied to a cell line which does not carry that variant allele. Anti-proliferative and pro-apoptotic effects of the siBRAFV600E -siNRASc.181C>A p.Q61Koccurs in a dose-dependent manner. A) Dose dependent effects of siBRAFV600E and siBRAFV600E- siNRASc.181C>A p.Q61Kcombination (siCOMBO) on proliferation in A2058 melanoma cells in vitro. Proliferation, by measurement of confluency, was quantified 4 days post transfection. B) Dose dependent effects of siBRAFV600E and siCOMBO on caspase 3 / 7 activity in A2058s. Caspase 3 / 7 activity was quantified 4 days post transfection. Concentration values for siCOMBO reflect the concentration of siBRAFV600E the siRNA cocktail. Cells were treated with a 3-fold serial dilution of siRNA in a concentration range of 50nM-0.006nM). The dilution and dispersion of siRNA was automating using the Echo550 liquid handler. Data is fitted to a sigmoidal (four-parameter logistic) dose-response curve; error bars ± SD, n=3. Figure 19: Addition of “redundant” siRNA does not reduce efficacy of variant-targeting siRNA, where redundant means a variant allele specific siRNA being applied to a cell line which does not carry that variant allele. Effect of siRNA NRASc.182A>G p.Q61Rand siCOMBO on cell viability in cell line derived from patient leptomeningeal melanoma (NRASc.182A>G p.Q61R) – demonstration of exquisite specificity of siRNAs targeting specific variant alleles – siCOMBO (siBRAF and siNRASc.181C>A p.Q61K) does not induce apoptosis whereas as siNRASc.182A>G p.Q61Rinduces apoptosis. A significant arrest of proliferation is observed by transfection with siNRAS NRASc.182A>G p.Q61Rand siCOMBO in comparison to siCTRL. A significant increase in the induction of apoptosis is observed with siNRAS Q1R but not with siCOMBO. A) Proliferation, determined by percentage confluency. B) Apoptosis, determined by Caspase 3 / 7 activity, was measured every 6 hours for 5 days. siRNA transfected at concentration of 25nM, or 50nM total siRNA for combination. Data shown as mean ± SD of triplicate wells. Assays were run in parallel on the same wells. Statistical differences between siCTRL and siNRAS NRASc.182A>G p.Q61Ror siCOMBO were examined using two-way-ANOVA, *p<0.05, ** p<0.01, ***p<0.001. Figure 20: Addition of “redundant” siRNA does not reduce efficacy of variant-targeting siRNA, where redundant means a variant allele specific siRNA being applied to a cell line which does not carry that variant allele. Effect of oncogene-targeting siRNAs, alone and in combination, on cell viability in Hermes-1 melanocytes. A) Proliferation analysis of determined by percentage confluency. B) Apoptosis analysis determined by Caspase 3 / 7 activity. Data shown as mean ± SD of triplicate wells. Statistical differences between siCTRL targeting-siRNAs were examined using two-way-ANOVA, *p<0.05, ** p<0.01, ***p<0.001, ****p<0.0001. C) Caspase 3 / 7 activity quantified at 96 hours. Concentrations of siRNA indicated in figure. Statistical differences between siCTRL and targeting siRNA examined by unpaired two-tailed t-test ****p<0.0001, n = 5. Figure 21: Allele-preferential siRNA KD of single oncogene and tumour suppressor gene variants induces apoptosis across cell lines in culture. SK-OV-3 ovarian cancer cell line: siRNA mutant- targeted KD is allele preferential and relatively spares WT expression. N=3. Figure 22: Allele-preferential siRNA KD of single oncogene and tumour suppressor gene variants induces apoptosis across cell lines in culture. SK-OV-3 ovarian cancer cell line: Single siPIK3CAc.3140A>G p.H1047Rmutant-targeted KD leads to reduction in cell confluency and KD of anti- apoptotic genes BIRC5 and BCL-2. N=1. A) siCNTRL IC50 = 39.61nM siPIK3CA IC50 = 5.97nM. B) EC50 = undetermined. C) D) E) T= 48 hours. All statistical tests were unpaired, two-tailed t-tests. Sig at p<0.05. Figure 23: Allele-preferential siRNA KD of single oncogene and tumour suppressor gene variants induces apoptosis across cell lines in culture. HCT-116 colonic carcinoma cell line: siRNA mutant- targeted KD is allele preferential, spares WT expression and leads to KD of ARL6IP1 and BIRC5. N=1. A) B) C) T= 48 hours. All statistical tests were unpaired, two-tailed t-tests. Sig at p<0.05. Figure 24: Allele-preferential siRNA KD of single oncogene and tumour suppressor gene variants induces apoptosis across cell lines in culture. HCT-116 colonic carcinoma cell line: Single oncogene variant-targeted KD leads to reduction in cell confluency and induction of apoptosis. N=1. A) siCNTRL IC50 = 58.04nM, siPIK3CA IC50 = 14.32nM. B) siCNTRL EC50 = Undetermined, siPIK3CA EC50 = 9.846nM. C) siCNTRL IC50 = 56.82nM, siKRAS EC50 = 17.42nM D) siCNTRL EC50 = 41.56nM, siKRAS EC50 = 6.377nM. All statistical tests were unpaired, two-tailed t-tests. Sig at p<0.05. Figure 25: Single tumour suppressor gene variant KD induces apoptosis across cell lines. SK-OV-3 ovarian cancer cell line: Single siFBXW7R505L mutant-targeted KD leads to reduction in cell confluency, induction of apoptosis and KD of anti-apoptotic genes at 50nM. N=1. A) siCNTRL IC50 = 28.13 siFBXW7 IC50 = 11.87 B) siCNTRL EC50 = undetermined, siFBXW7 EC50 = 13.07. C) D) E) T= 48 hours. All statistical tests were two-tailed, unpaired t-tests. Figure 26: HCT-116: Double targeted KDs (siMaGiC2) are superior to single siPIK3CAc.3140A>G p.H1047Rand allow for reduction of concentration in single components. N=1. A) siMaGiC2 IC50 = 2.298nM B) siMaGiC2 EC50 = 2.480nM. Figure 27: HCT-116 colonic cancer cell line: Double targeted KDs (siMaGiC2) are superior to single siKRASG13D and allow for reduction of concentration in single components. N=1. A) siMaGiC2 IC50 = 2.298nM B) siMaGiC2 EC50 = 2.480nM. Figure 28: Triple targeted KDs induce more apoptosis than double targeted across cell lines – the combination of three targeted allele-specific siRNAs can be more effective than combining two targeted allele-specific siRNAs. SK-OV-3 siMaGiC2 vs siMaGiC3 caspase 3 activity over 5 days. Statistical test was a repeated measures two-way ANOVA from 2-5 days. (N=3). Figure 29: In vivo data from mouse xenograft model of A2058 melanoma. Single siRNA treatment siBRAFV600Ein XG model of A2058 melanoma cell line, effective allele-preferential knockdown at 48 hours.1 dose at 2, 4 & 7 days. Figure 30: In vivo data from mouse xenograft model of A2058 melanoma. Single siRNA treatment siBRAFV600Ein XG model of A2058 melanoma cell line, despite knockdown wearing off after 48 hours, it has still triggered effect on tumour volume (trend).1 dose at 2, 4 & 7 days. Figure 31: In vivo data from mouse xenograft model of A2058 melanoma. Single siRNA treatment siBRAFV600Ein XG model of A2058 melanoma cell line – no H+E evidence of inflammation.1 dose at 2, 4 & 7 days. Figure 32: In vivo data from mouse xenograft model of SKOV3 ovarian cancer. MaGiC2 intra- tumoural injection in XG model of SKOV3 ovarian cancer line simultaneously knocks down both target variants effectively (50-60% KD) and induces significant apoptosis. One dose is sufficient to maintain knockdown at 4 days. NB FBXW7 is considered to be a tumour suppressor.1&2 doses. Tissue was analysed 4 days after the first dose. Mice receiving two doses received the second dose on day 2. Figure 33: In vivo data from mouse xenograft model of SKOV3 ovarian cancer. A) MaGiC2 intra- tumoural injection in XG model of SKOV3 ovarian cancer line demonstrates good allele preferential knockdown of both targets. A single dose is sufficient for seven days knockdown. B) Tumour volume showing trend to restriction in size with MaGiC2. Figure 34: In vivo data from mouse xenograft model of HCT116 colonic carcinoma. MaGiC3 (siMGC3- HCT116) intratumoural injection in XG model of HCT-116 human colon cancer line simultaneously knocks down three target variants. DETAILED DESCRIPTION Described herein is a novel approach to treating tumours in which pathogenic genomic sequence variants relevant to an individual’s tumour are targeted by combination treatment with multiple (at least two) nucleic acid molecules (such as siRNAs), with each nucleic acid molecule targeting a different pathogenic genomic sequence variant. The inventors term this approach MaGiC (Multi-targeted Genetic therapy for Cancer). Important differences between MaGiC and previous approaches include the use of multiple siRNAs, use of siRNAs preferentially targeting variant alleles (rather than targeting non-variant genes), lower doses of individual siRNAs that can be used as a result of the combinatorial approach, and the proven efficacy in inducing apoptosis in tumour cells demonstrated by the inventors using this approach. The inventors provide experimental data from variant-allele-specific siRNA targeting of oncogene- driven monogenic diseases which demonstrate induction of cell intrinsic apoptosis and growth arrest in patient cells, and both superiority over existing signalling pathway targeted drugs, and synergy with those drugs. Furthermore, the specificity of action of the combination therapies described herein renders it simultaneously both the therapeutic and the tumour targeting system. The MaGiC approach can optionally be combined with sequencing of a subject’s tumour or cell free DNA / RNA to determine the precise pathogenic genomic sequence variants present, and subsequently designing a personalised treatment using siRNAs targeting those variants. As MaGiC is agnostic of cancer type, the combination of liquid biopsy driver detection and MaGiC therapy could bypass the need for tumour identification in cases where the primary is not known. Sequencing at depth can also be used to detect variants at lower variant allele frequencies. Such variants may be important clinically as they may be present in subclones having mutational profiles which are distinct from the main clonal line in the tumour. Such subclones can lead to treatment resistance, recurrence or metastasis. Accordingly, any of the methods described herein may comprise deep sequencing of a patient’s tumour, such as ultra-deep sequencing. As there are fewer genetic alterations earlier in cancer progression, and oncogenic variants arguably contribute more to the phenotype in those stages, MaGiC can be used as a treatment for earlier stage tumours where outcomes are poor on current standard of care. The treatment of subclone low allele frequency oncogenic variants at the same time as the principal drivers in earlier stage tumours may in particular prevent recurrence better than standard of care. MaGiC may also be useful for later stage tumours where standard treatment is poor, as the large scale copy number changes which take place such as aneuploidy and whole genome duplication continue to preserve the drivers. Furthermore, there is more oncogenic variant variability in metastases than there is in primary tumours due to multi- clonal evolution, and the MaGiC approach may therefore improve outcome compared to standard of care in that context. Various advantages of the MaGiC approach are set out below: 1) MaGiC is intrinsically both the therapeutic and the tumour targeting system; 2) MaGiC exploits normal homeostatic mechanisms to apoptose or arrest tumour cells, with data showing these are cell-intrinsic effects, not immunological; 3) MaGiC can be highly personalised and highly stage-specific, but it is agnostic to cancer type and to stage of tumour progression, allowing maximum flexibility and wide applicability. The invention provides various methods that are useful in the treatment of tumours. Generally, the methods comprise the selection of at least two different pathogenic genomic sequence variants that are relevant to a tumour of a subject, and the provision of at least two nucleic acid molecules that can each target one of the identified variants. The approaches described herein can be used to prepare a combinatorial treatment suitable for suppressing growth of and / or inducing apoptosis in a tumour in a subject, for determining a treatment regimen for treating a tumour in a subject, for inducing apoptosis in a tumour of a subject, for treating a tumour in a subject, and for treating a cancer in a subject, among others. Described herein is a method of preparing a combinatorial treatment suitable for suppressing growth and / or inducing apoptosis in a tumour of a subject, the method comprising: c) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; and d) providing a first nucleic acid molecule complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); thereby providing the combinatorial treatment. Also described herein is a method of determining a treatment regimen for treating a tumour in a subject; the method comprising: c) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; and d) providing a first nucleic acid molecule complementary to an mRNA encoding a first pathogenic genomic sequence variant relevant to the tumour of the subject identified in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); thereby providing the treatment regimen. Also described herein is a method of inducing apoptosis in a tumour of a subject, the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; b) providing a first nucleic acid molecule complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); and c) administering the first and second nucleic acid molecules to the subject. Also described herein is method of treating a tumour in a subject, the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; b) providing a first nucleic acid molecule complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); and c) administering the first and second nucleic acid molecules to the subject. Provided herein is a composition comprising at least two nucleic acid molecules, wherein the composition is suitable for inducing apoptosis in a tumour in a subject, wherein a first nucleic acid molecule comprises a sequence that is complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject, and each further nucleic acid molecule comprises a sequence that is complementary to an mRNA of a different pathogenic genomic sequence variant relevant to the tumour of the subject. Provided herein is a combination comprising at least two nucleic acid molecules, wherein the combination is suitable for inducing apoptosis in a tumour in a subject, wherein a first nucleic acid molecule comprises a sequence that is complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject, and each further nucleic acid molecule comprises a sequence that is complementary to an mRNA of a different pathogenic genomic sequence variant relevant to the tumour of the subject. Any of the methods, compositions and combinations described herein may be subject to the proviso that the method, composition or combination does not comprise both a nucleic acid molecule that is complementary to a variant NRAS mRNA, and a nucleic acid molecule that is complementary to a variant BRAF mRNA. Any of the methods, compositions and combinations described herein may be subject to the proviso that the method, composition or combination does not comprise both a nucleic acid molecule that is complementary to a variant GNAQ mRNA, and a nucleic acid molecule that is complementary to a variant GNA11 mRNA. The term “tumour” as used herein includes the full spectrum of tumours, from benign to malignant, as well as all stages of malignant tumours. Accordingly, the term “tumour” as used herein encompasses both cancerous and non-cancerous tumours. The term “pathogenic genomic sequence variant” as used herein refers to variant or mutated forms of genes which are known or suspected to have a pathogenic effect, in particular an oncogenic or tumour-promoting effect (including variant or mutated forms of oncogenes and tumour suppressor genes). They include both gain of function and loss of function variants. For example, in the case of NRAS, variants include those variants having mutations or sequence variability relative to wild type at positions G60, Q61, G12 and / or G13 (among others), such as the well known NRAS Q61K variant (e.g., NRASc.181C>A p.Q61K). The term “relevant to the tumour” includes variants which are expressed by the tumour at the DNA, RNA or protein level, as well as variants which are known to be commonly associated with a tumour of the subject’s type. For example, the subject may have an ovarian tumour. Pathogenic genomic sequence variants relevant to ovarian tumours include variant / mutated forms of TP53, KRAS, FOXL2, PIK3CA, and BRAF among others, which are known to be commonly present in ovarian tumours. Similarly, pathogenic genomic sequence variants relevant to breast cancer include variant / mutated forms of PIK3CA, TP53, CDH1, MED12, ESR1, GATA3, KMT2C and MAP3K1, among others. Each different pathogenic genomic sequence variant may be expressed by the tumour of the subject. “Selecting” the variants can involve determining which variants are expressed by the tumour at the DNA, RNA or protein level, for example by genotyping or sequencing the tumour of the subject. However, selecting the variants does not necessarily require confirmation (e.g. by genotyping) that a variant is expressed by the tumour. It is also possible to select variants based on the skilled person’s common general knowledge about which variants are commonly associated with a tumour of the subject’s type. Various publicly available databases, such as the Cancer Gene Census (part of the COSMIC database provide information on mutated genes which are commonly expressed by various tumour types. In this way, the skilled person can predict which variants are likely to be present in the tumour of the subject, and select said variants for use in the methods described herein. The methods, compositions and combinations described herein include the provision of nucleic acid molecules complementary to an mRNA of a pathogenic genomic sequence variant. Such mRNAs are those that are transcribed from or have a corresponding sequence to the pathogenic genomic sequence variant. By providing a nucleic acid molecule complementary to an mRNA of a pathogenic genomic sequence variant, expression of the mRNA can be inhibited, reduced or prevented. This may further be accompanied by changes (i.e. reductions) in expression levels of a corresponding protein. As shown in the experimental examples provided herein, mRNA targeting using the MaGiC approach can inhibit proliferation and produce apoptosis of cancer cells. Any of the methods described herein may further comprise providing one or more further nucleic acid molecules, wherein each further nucleic acid molecule is complementary to an mRNA of a further pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a), and administering each further nucleic acid molecule to the subject. Similarly, any of the compositions or combinations described herein may also comprise further nucleic acid molecules that are complementary to an mRNA of further pathogenic genomic sequence variants, in addition to the first and second nucleic acid molecules already described. Any of the methods described herein may further comprise a step of providing sequence information for the tumour of the subject, prior to any selecting step in which pathogenic genomic sequence variants are selected. The step of selecting pathogenic genomic sequence variants may then comprise selecting the at least two different pathogenic genomic sequence variants on the basis of the sequence information. Sequence information for the tumour of the subject may be obtained from genotyping a sample of the subject’s tumour. For example, by sequencing a sample of the subject’s tumour. Sequence information for the tumour of the subject may also be provided by liquid biopsy, i.e. the detection and sequencing of cell free DNA / RNA. Alternatively or additionally, sequence information for the tumour of the subject may be obtained from a database, such as the publicly available COSMIC database The step of selecting pathogenic genomic sequence variants as described herein may comprise sequencing a cell free RNA sample or a cell free DNA sample from the subject. The step of selecting pathogenic genomic sequence variants as described herein may comprise sequencing a sample obtained from the tumour of the subject. Sequencing as referred to herein may include ultra-deep sequencing and / or massively parallel sequencing-by-synthesis. The step of selecting pathogenic genomic sequence variants as described herein may comprise identifying at least one (in some cases, at least two, at least three, at least four, or more) pathogenic genomic sequence variants relevant to the tumour of the subject based on known pathogenic genomic sequence variants for the same or similar tumour types. In any of the methods described herein, the step of selecting pathogenic genomic sequence variants as described herein may comprise identifying at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten pathogenic genomic sequence variants relevant to the tumour of the subject. Said selecting step may comprise identifying at least three, at least four, at least five, at least six, or at least seven pathogenic genomic sequence variants relevant to the tumour of the subject. The tumour of the subject may be a benign tumour. The tumour may be a malignant tumour. The tumour may be a dysplastic lesion. The tumour may be a benign congenital tumour. The tumour may be a cancerous tumour. The tumour may be a solid tumour. The tumour may be a congenital melanocytic naevus. The tumour may be an arteriovenous malformation (AVM). The tumour may be an acquired naevus. The tumour may be a lung, brain, bladder, endometrial, kidney, heart, ovarian, stomach, throat, mouth, head, neck, skin, pancreas, rectal, colon, penile, eye, connective tissue, fat, bone, prostate, thyroid, uterine, or liver tumour, or a combination thereof. The approaches described herein may be applied to the treatment of cancer. The cancer may be selected from the group consisting of the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid lukemia (AML), adrenocortical carcinoma, Kaposi sarcoma, AIDS-related lymphoma, primary CNS lymphoma, anal cancer, appendix cancer, astrocytoma, brain cancer, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, breast cancer, Burkitt lymphoma, carcinoma, medulloblastoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocyte leukemia, chronic myelogenous leukemia, chronic myeloproliferative neoplasm, colorectal cancer, craniopharyngioma, ductal carcinoma, endometrial cancer, ependymoma, esophageal cancer, head and neck cancer, Ewing sarcoma, eye cancer, fallopian tube cancer, gallbladder cancer, gastric cancer, stomach cancer, leukemia, blood cancer, hepatocellular cancer, liver cancer, kidney cancer, lip cancer, lymphoma, laryngeal cancer, lung cancer, melanoma (for example, leptomeningeal melanocytic disease), merkel cell carcinoma, mesothelioma, mouth cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous neck cancer, stomach cancer, urethral cancer, uterine cancer, vaginal cancer, vascular cancer, vulvar cancer or a combination thereof. As noted above, at least one of the pathogenic genomic sequence variants may be a gain of function variant. At least one of the pathogenic genomic sequence variants may be a loss of function variant. The tumour may be heterozygous for the loss of function variant. In some cases, the pathogenic genomic sequence variants relevant to the tumour of the subject comprise a mix of gain of function and loss of function variants. For example, a first nucleic acid molecule may be provided which is complementary to an mRNA of a gain of function pathogenic genomic sequence variant, and a second nucleic acid molecule may be provided which is complementary to an mRNA of a loss of function pathogenic genomic sequence variant. The nucleic acid molecules described herein may be allele specific, in that they preferentially target an mRNA of a pathogenic genomic sequence variant relative to an mRNA of a non-variant or non- mutated sequence of the same gene. By way of example, a nucleic acid molecule may preferentially target (bind to and inhibit the expression of) NRAS Q61K (e.g., NRASc.181C>A p.Q61K) relative to wild type (non-variant / non-mutated) NRAS. The nucleic acid molecules (one, two, and / or each further nucleic acid molecules) may therefore preferentially hybridise to an mRNA of a pathogenic genomic sequence variant relative to an mRNA of a non-variant sequence of the same gene. In some cases, the nucleic acid molecules (one, two, and / or each further nucleic acid molecules) may preferentially hybridise to an mRNA of an oncogenic genomic sequence variant relative to an mRNA of a non-variant sequence of the same gene. The nucleic acid molecules (one, two, and / or each further nucleic acid molecules) may preferentially inhibit the expression of a pathogenic genomic sequence variant relative to a non- variant sequence of the same gene. The nucleic acid molecules (one, two, and / or each further nucleic acid molecules) may preferentially inhibit the expression of an oncogenic genomic sequence variant relative to a non-variant sequence of the same gene. Nucleic acid molecules for use in the invention can be designed that target a cluster of pathogenic genomic sequence variants, in particular those variants that occur in the same codon or very nearby. For example, a nucleic acid molecule may preferentially target mRNAs of at least two (e.g. two, three or more) pathogenic genomic sequence variants relative to an mRNA of a non-variant or non-mutated sequence of the same gene. For example, a nucleic acid molecule may preferentially target mRNAs of at least two (e.g. two, three or more) oncogenic genomic sequence variants relative to an mRNA of a non-variant or non-mutated sequence of the same gene. A nucleic acid molecule may preferentially hybridise to mRNAs of at least two (for example two, three, or more) pathogenic genomic sequence variants relative to a non-variant sequence of the same gene. A nucleic acid molecule may preferentially hybridise to mRNAs of at least two (for example two, three, or more) oncogenic genomic sequence variants relative to a non-variant sequence of the same gene. A nucleic acid molecule may preferentially inhibit the expression of at least two (for example two, three, or more) pathogenic genomic sequence variants relative to a non-variant sequence of the same gene. A nucleic acid molecule may preferentially inhibit the expression of at least two (for example two, three, or more) oncogenic genomic sequence variants relative to a non-variant sequence of the same gene. The methods, compositions and combinations described herein may comprise providing at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten nucleic acid molecules. In some cases, step (b) of the methods described herein comprises providing at least three nucleic acid molecules (each of them able to inhibit the expression of a different pathogenic genomic sequence variant). Each of the first, second and further nucleic acid molecules as described herein may independently be 10 to 50, 10 to 40, 10 to 30, 10 to 20, 15 to 30, 15 to 25, 20 to 30, 20 to 25, or 21 nucleotides in length. In some cases, both the first and second nucleic acid molecules are 10 to 50, 10 to 40, 10 to 30, 10 to 20, 15 to 30, 15 to 25, 20 to 30, 20 to 25, or 21 nucleotides in length. Each of the first, second and further nucleic acid molecules as described herein may be a double stranded nucleic acid molecule. For example, the first nucleic acid molecule may comprise a first strand that is complementary to at least a portion of the mRNA of the first pathogenic genomic sequence variant, and further comprise a second strand complementary to the first strand. The second nucleic acid molecule may comprise a first strand that is complementary to at least a portion of the mRNA of the second pathogenic genomic sequence variant, and further comprise a second strand complementary to the first strand. Each further nucleic acid molecule may also be double stranded. Each of the first, second and further nucleic acid molecules as described herein may be an siRNA. In any of the methods described herein, the nucleic acid molecules (for example, the first and second nucleic acid molecules) may be suitable for simultaneous administration. The nucleic acid molecules may be suitable for sequential administration, in any order. In any of the methods and compositions described herein, the nucleic acid molecules (for example, the first, second and any further nucleic acid molecules) may be formulated in a single composition. Alternatively, they may be formulated in separate compositions. It is also permissible for a first and second nucleic acid molecule to be formulated in a single composition, and for further nucleic acid molecules to be provided separately. The concentrations of each of the nucleic acid molecules need not be equal. For example, in any of the methods, compositions or combinations described herein, a first nucleic acid molecule may be administered at a higher concentration than a second nucleic acid molecule, or vice versa. While the approaches described herein can be used to provide a highly personalised combination treatment based on sequence information from the subject (e.g. from sequencing the tumour), most cancers (or tumours) tend to have 1-3 recurrent genes which acquire oncogenic variants in most patients (Li X. Dynamic changes of driver genes' mutations across clinical stages in nine cancer types. Cancer Med.2016;5(7):1556-65). Accordingly, the approaches described herein can also comprise a combination of 2, 3, or more nucleic acid molecules targeting variants which are known or predicted to be commonly expressed in a specific cancer type. For example, pathogenic genomic sequence variants associated with breast cancer may include variants of PIK3CA (for example, PIK3CAc.3140A>G p.H1047Ror PIK3CAc.1633G>A p.E545K), TP53, CDH1, MED12, ESR1, GATA3 (for example, c.1006dupG p.D336Gfs*17), KMT2C, MAP3K1, PTEN, LRP1B, ERBB4, NF1, ZFHX3, ERBB2, AKT1, ARID1A, ALK, PTPRT, RUNX1 and / or BRCA2. Where the methods, compositions or combinations as described herein are intended to treat or induce apoptosis in a breast tumour or breast cancer tumour, at least two nucleic acid molecules may be provided which are complementary to mRNAs of at least two different variants from this list. For example, a first nucleic acid molecule may be complementary to an mRNA of variant PIK3CA, and a second nucleic acid molecule may be complementary to an mRNA of variant TP53. A first nucleic acid molecule may be complementary to an mRNA of variant PIK3CA, a second nucleic acid molecule may be complementary to an mRNA of variant TP53, and a third nucleic acid molecule may be complementary to an mRNA of variant CDH1. A first nucleic acid molecule may be complementary to an mRNA of variant PIK3CA, a second nucleic acid molecule may be complementary to an mRNA of variant CDH1. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, a second nucleic acid molecule may be complementary to an mRNA of variant CDH1. Optional further nucleic acid molecules may be complementary to an mRNA of variants of PIK3CA, TP53, CDH1, MED12, ESR1, GATA3, KMT2C, MAP3K1, PTEN, LRP1B, ERBB4, NF1, ZFHX3, ERBB2, AKT1, ARID1A, ALK, PTPRT, RUNX1 and / or BRCA2. Pathogenic genomic sequence variants associated with lung cancer may include variants of EGFR, KRAS (for example, c.38G>A p.G13D), TP53, LRP1B, PIK3CA (for example, PIK3CAc.3140A>G p.H1047Ror PIK3CAc.1633G>A p.E545K), STK11, KEAP1, BRAF (for example, p.V600E), MET, RB1, KMT2D, ARID1A, KMT2C, NF1, FAT1, ALK, ERBB2, SMARCA4, ATM and / or CDKN2A. Where the methods, compositions or combinations as described herein are intended to treat or induce apoptosis in a lung tumour or lung cancer tumour, a first nucleic acid molecule may be complementary to an mRNA of variant TP53, and a second nucleic acid molecule may be complementary to an mRNA of variant LRP1B. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, and a second nucleic acid molecule may be complementary to an mRNA of variant EGFR. A first nucleic acid molecule may be complementary to an mRNA of variant EGFR, and a second nucleic acid molecule may be complementary to an mRNA of variant LRP1B. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, a second nucleic acid molecule may be complementary to an mRNA of variant LRP1B, and a third nucleic acid molecule may be complementary to an mRNA of variant EGFR. Optional further nucleic acid molecules may be complementary to an mRNA of variants of EGFR, KRAS, TP53, LRP1B, PIK3CA, STK11, KEAP1, BRAF, MET, RB1, KMT2D, ARID1A, KMT2C, NF1, FAT1, ALK, ERBB2, SMARCA4, ATM and / or CDKN2A. Pathogenic genomic sequence variants associated with bowel cancer may include variants of KRAS (for example, c.38G>A p.G13D), BRAF (for example, p.V600E), TP53, APC (for example, c.4666del p.T1556fs), PIK3CA (for example, PIK3CAc.3140A>G p.H1047Ror PIK3CAc.1633G>A p.E545K), FBXW7 (for example, c.1514G>T p.R505L), SMAD4, RNF43, LRP1B, CTNNB1 (for example, CTNNB1c.133_135delTCT(for example, NRASp.Q61K, such as NRASc.181C>A p.Q61K, or NRASp.Q61R, such as KMT2C, ATM, KMT2D, PTEN, ARID1A, GNAS and / or AMER1. Where the methods, compositions or combinations as described herein are intended to treat or induce apoptosis in a bowel tumour or bowel cancer tumour, a first nucleic acid molecule may be complementary to an mRNA of variant APC, and a second nucleic acid molecule may be complementary to an mRNA of variant TP53. A first nucleic acid molecule may be complementary to an mRNA of variant APC, and a second nucleic acid molecule may be complementary to an mRNA of variant KRAS. A first nucleic acid molecule may be complementary to an mRNA of variant APC, and a second nucleic acid molecule may be complementary to an mRNA of variant FAT4. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, and a second nucleic acid molecule may be complementary to an mRNA of variant KRAS. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, and a second nucleic acid molecule may be complementary to an mRNA of variant FAT4. A first nucleic acid molecule may be complementary to an mRNA of variant APC, a second nucleic acid molecule may be complementary to an mRNA of variant TP53, and a third nucleic acid molecule may be complementary to an mRNA of variant KRAS. Optional further nucleic acid molecules may be complementary to an mRNA of variants of KRAS, BRAF, TP53, APC, PIK3CA, FBXW7, SMAD4, RNF43, LRP1B, CTNNB1, FAT4, NRAS, TCF7L2, KMT2C, ATM, KMT2D, PTEN, ARID1A, GNAS and / or AMER1. Pathogenic genomic sequence variants associated with prostate cancer may include variants of TP53, LRP1B, ERBB4, ALK, ATR, AR, ZFHX3, ATM, PTPRT, FHIT, APC (for example, c.4666del p.T1556fs), GRIN2A, SPOP, KMT2C, PTEN, RAD51B, SMARCA4, CAMTA1, NOTCH2 and / or NF1. Where the methods, compositions or combinations as described herein are intended to treat or induce apoptosis in a prostate tumour or prostate cancer tumour, a first nucleic acid molecule may be complementary to an mRNA of variant LRP1B, and a second nucleic acid molecule may be complementary to an mRNA of variant TP53. A first nucleic acid molecule may be complementary to an mRNA of variant LRP1B, and a second nucleic acid molecule may be complementary to an mRNA of variant ERBB4. A first nucleic acid molecule may be complementary to an mRNA of variant LRP1B, and a second nucleic acid molecule may be complementary to an mRNA of variant FHIT. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, and a second nucleic acid molecule may be complementary to an mRNA of variant ERBB4. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, and a second nucleic acid molecule may be complementary to an mRNA of variant FHIT. A first nucleic acid molecule may be complementary to an mRNA of variant ERBB4, and a second nucleic acid molecule may be complementary to an mRNA of variant FHIT. A first nucleic acid molecule may be complementary to an mRNA of variant LRP1B, a second nucleic acid molecule may be complementary to an mRNA of variant TP53, and a third nucleic acid molecule may be complementary to an mRNA of variant ERBB4. Optional further nucleic acid molecules may be complementary to an mRNA of variants of TP53, LRP1B, ERBB4, ALK, ATR, AR, ZFHX3, ATM, PTPRT, FHIT, APC, GRIN2A, SPOP, KMT2C, PTEN, RAD51B, SMARCA4, CAMTA1, NOTCH2 and / or NF1. Pathogenic genomic sequence variants associated with skin cancer may include variants of BRAF (for example, p.V600E), NRAS (for example, NRASp.Q61K, such as NRASc.181C>A p.Q61K, or NRASp.Q61R, such as NRASc.182A>G p.Q61R), TP53, GRIN2A, LRP1B, ROS1, ERBB4, KIT, NF1, PREX2, PTCH1, HRAS, KMT2D, CDKN2A, KMTC, NOTCH1, KDR, PTPRT, FAT4 and / or NOTCH2. Where the methods, compositions or combinations as described herein are intended to treat or induce apoptosis in a skin tumour or skin cancer tumour, a first nucleic acid molecule may be complementary to an mRNA of variant BRAF, and a second nucleic acid molecule may be complementary to an mRNA of variant LRP1B. A first nucleic acid molecule may be complementary to an mRNA of variant BRAF, and a second nucleic acid molecule may be complementary to an mRNA of variant GRIN2A. A first nucleic acid molecule may be complementary to an mRNA of variant BRAF, and a second nucleic acid molecule may be complementary to an mRNA of variant TP53. A first nucleic acid molecule may be complementary to an mRNA of variant BRAF, and a second nucleic acid molecule may be complementary to an mRNA of variant FAT4. A first nucleic acid molecule may be complementary to an mRNA of variant LRP1B, and a second nucleic acid molecule may be complementary to an mRNA of variant GRIN2A. A first nucleic acid molecule may be complementary to an mRNA of variant LRP1B, and a second nucleic acid molecule may be complementary to an mRNA of variant TP53. A first nucleic acid molecule may be complementary to an mRNA of variant LRP1B, and a second nucleic acid molecule may be complementary to an mRNA of variant FAT4. A first nucleic acid molecule may be complementary to an mRNA of variant BRAF, a second nucleic acid molecule may be complementary to an mRNA of variant LRP1B, and a third nucleic acid molecule may be complementary to an mRNA of variant GRIN2A. Optional further nucleic acid molecules may be complementary to an mRNA of variants of BRAF, NRAS, TP53, GRIN2A, LRP1B, ROS1, ERBB4, KIT, NF1, PREX2, PTCH1, HRAS, KMT2D, CDKN2A, KMTC, NOTCH1, KDR, PTPRT, FAT4 and / or NOTCH2. Pathogenic genomic sequence variants associated with ovarian cancer may include variants of TP53, KRAS (for example, c.38G>A p.G13D), FOXL2, PIK3CA (for example, PIK3CAc.3140A>G p.H1047Ror PIK3CAc.1633G>A p.E545K), BRAF (for example, p.V600E), ARID1A, CTNNB1 (for example, CTNNB1c.133_135delTCT p.S45Del), PTEN, LRP1B, BRCA1, PTPRT, BRCA1, KMT2C, ZFHX3, DICER1, ATM, NF1, ALK, NTRK3 and / or CAMTA1. Where the methods, compositions or combinations as described herein are intended to treat or induce apoptosis in an ovarian tumour or ovarian cancer tumour, a first nucleic acid molecule may be complementary to an mRNA of variant TP53, and a second nucleic acid molecule may be complementary to an mRNA of variant FOXL2. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, and a second nucleic acid molecule may be complementary to an mRNA of variant ARID1A. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, and a second nucleic acid molecule may be complementary to an mRNA of variant KRAS. A first nucleic acid molecule may be complementary to an mRNA of variant FOXL2, and a second nucleic acid molecule may be complementary to an mRNA of variant ARID1A. A first nucleic acid molecule may be complementary to an mRNA of variant FOXL2, and a second nucleic acid molecule may be complementary to an mRNA of variant KRAS. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, a second nucleic acid molecule may be complementary to an mRNA of variant FOXL2, and a third nucleic acid molecule may be complementary to an mRNA of variant ARID1A. Optional further nucleic acid molecules may be complementary to an mRNA of variants of TP53, KRAS, FOXL2, PIK3CA, BRAF, ARID1A, CTNNB1, PTEN, LRP1B, BRCA1, PTPRT, BRCA2, KMT2C, ZFHX3, DICER1, ATM, NF1, ALK, NTRK3 and / or CAMTA1. Pathogenic genomic sequence variants may include variants of CDH1, MED12, ESR1, GATA3 (for example, c.1006dupG p.D336Gfs*17), KMT2C, MAP3K1, PTEN, LRP1B, ERBB4, NF1, ZFHX3, ERBB2, AKT1, ARID1A, ALK, PTPRT, RUNX1, BRCA2, EGFR, KRAS, TP53, LRP1B, PIK3CA (for example, PIK3CAc.3140A>G p.H1047Ror PIK3CAc.1633G>A p.E545K), STK11, KEAP1, MET, RB1, KMT2D, ARID1A, KMT2C, FAT1, ALK, SMARCA4, CDKN2A, KRAS, BRAF (for example, p.V600E), APC (for example, c.4666del p.T1556fs), FBXW7 (for example, c.1514G>T p.R505L), SMAD4, RNF43, CTNNB1 (for example, CTNNB1c.133_135delTCT p.S45Del), FAT4, NRAS (for example, NRASp.Q61K, such as NRASc.181C>A p.Q61K, or NRASp.Q61R, such as NRASc.182A>G p.Q61R), TCF7L2, KMT2C, ATM, KMT2D, GNAS, AMER1, ATR, AR, ZFHX3, ATM, PTPRT, FHIT, GRIN2A, SPOP, RAD51B, CAMTA1, MYC, NOTCH2, GRIN2A, ROS1, KIT, PREX2, PTCH1, HRAS, KDR, DICER1, FOXL2, NTRK3 and / or CAMTA1. A first nucleic acid molecule may be complementary to an mRNA of variant PIK3CA, and a second nucleic acid molecule may be complementary to an mRNA of variant TP53. A first nucleic acid molecule may be complementary to an mRNA of variant PIK3CA, a second nucleic acid molecule may be complementary to an mRNA of variant TP53, and a third nucleic acid molecule may be complementary to an mRNA of variant CDH1. A first nucleic acid molecule may be complementary to an mRNA of variant PIK3CA, a second nucleic acid molecule may be complementary to an mRNA of variant CDH1. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, a second nucleic acid molecule may be complementary to an mRNA of variant CDH1. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, and a second nucleic acid molecule may be complementary to an mRNA of variant LRP1B. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, and a second nucleic acid molecule may be complementary to an mRNA of variant EGFR. A first nucleic acid molecule may be complementary to an mRNA of variant EGFR, and a second nucleic acid molecule may be complementary to an mRNA of variant LRP1B. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, a second nucleic acid molecule may be complementary to an mRNA of variant LRP1B, and a third nucleic acid molecule may be complementary to an mRNA of variant EGFR. A first nucleic acid molecule may be complementary to an mRNA of variant APC, and a second nucleic acid molecule may be complementary to an mRNA of variant TP53. A first nucleic acid molecule may be complementary to an mRNA of variant APC, and a second nucleic acid molecule may be complementary to an mRNA of variant KRAS. A first nucleic acid molecule may be complementary to an mRNA of variant APC, and a second nucleic acid molecule may be complementary to an mRNA of variant FAT4. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, and a second nucleic acid molecule may be complementary to an mRNA of variant KRAS. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, and a second nucleic acid molecule may be complementary to an mRNA of variant FAT4. A first nucleic acid molecule may be complementary to an mRNA of variant APC, a second nucleic acid molecule may be complementary to an mRNA of variant TP53, and a third nucleic acid molecule may be complementary to an mRNA of variant KRAS. A first nucleic acid molecule may be complementary to an mRNA of variant LRP1B, and a second nucleic acid molecule may be complementary to an mRNA of variant TP53. A first nucleic acid molecule may be complementary to an mRNA of variant LRP1B, and a second nucleic acid molecule may be complementary to an mRNA of variant ERBB4. A first nucleic acid molecule may be complementary to an mRNA of variant LRP1B, and a second nucleic acid molecule may be complementary to an mRNA of variant FHIT. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, and a second nucleic acid molecule may be complementary to an mRNA of variant ERBB4. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, and a second nucleic acid molecule may be complementary to an mRNA of variant FHIT. A first nucleic acid molecule may be complementary to an mRNA of variant ERBB4, and a second nucleic acid molecule may be complementary to an mRNA of variant FHIT. A first nucleic acid molecule may be complementary to an mRNA of variant LRP1B, a second nucleic acid molecule may be complementary to an mRNA of variant TP53, and a third nucleic acid molecule may be complementary to an mRNA of variant ERBB4. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, and a second nucleic acid molecule may be complementary to an mRNA of variant FOXL2. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, and a second nucleic acid molecule may be complementary to an mRNA of variant ARID1A. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, and a second nucleic acid molecule may be complementary to an mRNA of variant KRAS. A first nucleic acid molecule may be complementary to an mRNA of variant FOXL2, and a second nucleic acid molecule may be complementary to an mRNA of variant ARID1A. A first nucleic acid molecule may be complementary to an mRNA of variant FOXL2, and a second nucleic acid molecule may be complementary to an mRNA of variant KRAS. A first nucleic acid molecule may be complementary to an mRNA of variant TP53, a second nucleic acid molecule may be complementary to an mRNA of variant FOXL2, and a third nucleic acid molecule may be complementary to an mRNA of variant ARID1A. A first nucleic acid molecule may be complementary to an mRNA of variant NRAS, and a second nucleic acid molecule may be complementary to an mRNA of variant MYC. A first nucleic acid molecule may be complementary to an mRNA of variant PIK3CA, and a second nucleic acid molecule may be complementary to an mRNA of variant GATA3. A first nucleic acid molecule may be complementary to an mRNA of variant PIK3CA2 (PIK3CAc.1633G>A p.E545K), and a second nucleic acid molecule may be complementary to an mRNA of variant GATA3. A first nucleic acid molecule may be complementary to an mRNA of variant PIK3CA1 (PIK3CAc.3140A>G p.H1047R), and a second nucleic acid molecule may be complementary to an mRNA of variant FBXW7. A first nucleic acid molecule may be complementary to an mRNA of variant PIK3CA2 (PIK3CAc.1633G>A p.E545K), and a second nucleic acid molecule may be complementary to an mRNA of variant GATA3. A first nucleic acid molecule may be complementary to an mRNA of variant PIK3CA, a second nucleic acid molecule may be complementary to an mRNA of variant FBXW7, and a third nucleic acid molecule may be complementary to an mRNA of variant APC. A first nucleic acid molecule may be complementary to an mRNA of variant PIK3CA1 (PIK3CAc.3140A>G p.H1047R), a second nucleic acid molecule may be complementary to an mRNA of variant FBXW7, and a third nucleic acid molecule may be complementary to an mRNA of variant APC. A first nucleic acid molecule may be complementary to an mRNA of PIK3CAc.3140A>G p.H1047R, and a second nucleic acid molecule may be complementary to an mRNA of CTNNB1c.133_135delTCT p.S45Del. A first nucleic acid molecule may be complementary to an mRNA of PIK3CAc.3140A>G p.H1047R, and a second nucleic acid molecule may be complementary to an mRNA of KRASc.38G>A p.G13D. A first nucleic acid molecule may be complementary to an mRNA of PIK3CAc.3140A>G p.H1047R, a second nucleic acid molecule may be complementary to an mRNA of KRASc.38G>A p.G13D, and a third nucleic acid molecule may be complementary to an mRNA of CTNNB1c.133_135delTCT p.S45Del. A first nucleic acid molecule may be complementary to an mRNA of PIK3CAc.3140A>G p.H1047R, and a second nucleic acid molecule may be complementary to an mRNA of FBXW7c.1514G>T p.R505L. A first nucleic acid molecule may be complementary to an mRNA of PIK3CAc.3140A>G p.H1047R, a second nucleic acid molecule may be complementary to an mRNA of FBXW7c.1514G>T p.R505L, and a third nucleic acid molecule may be complementary to an mRNA of APCc.4666del p.T1556fs. A first nucleic acid molecule may be complementary to an mRNA of PIK3CAc.1633G>A p.E545K, and a second nucleic acid molecule may be complementary to an mRNA of GATA3c.1006dupG p.D336Gfs*17A first nucleic acid molecule may be complementary to an mRNA of NRASp.Q61K(for example, NRASc.181C>A p.Q61K), a second nucleic acid molecule may be complementary to an mRNA of NRASp.Q61R(for example, NRASc.182A>G p.Q61R), and a third nucleic acid molecule may be complementary to an mRNA of BRAFp.V600E. An exemplary combination of nucleic acid molecules may be nucleic acid molecules that target variant PIK3CA, FBXW7 and APC. The nucleic acid molecules may be double stranded. The nucleic acid molecule targeting variant PIK3CA may comprise a first strand having a sequence set forth in SEQ ID NO: 1, and a second strand having a sequence set forth in SEQ ID NO: 2. The nucleic acid molecule targeting variant PIK3CA may comprise a first strand having a sequence set forth in SEQ ID NO: 155, and a second strand having a sequence set forth in SEQ ID NO: 156. The nucleic acid molecule targeting variant PIK3CA may comprise a first strand having a sequence set forth in SEQ ID NO: 5, and a second strand having a sequence set forth in SEQ ID NO: 6. The nucleic acid molecule targeting variant PIK3CA may comprise a first strand having a sequence set forth in SEQ ID NO: 159, and a second strand having a sequence set forth in SEQ ID NO: 160. The nucleic acid molecule targeting variant FBXW7 may comprise a first strand having a sequence set forth in SEQ ID NO: 7, and a second strand having a sequence set forth in SEQ ID NO: 8. The nucleic acid molecule targeting variant FBXW7 may comprise a first strand having a sequence set forth in SEQ ID NO: 161, and a second strand having a sequence set forth in SEQ ID NO: 162. The nucleic acid molecule targeting variant APC may comprise a first strand having a sequence set forth in SEQ ID NO: 9, and a second strand having a sequence set forth in SEQ ID NO: 10. The nucleic acid molecule targeting variant APC may comprise a first strand having a sequence set forth in SEQ ID NO: 163, and a second strand having a sequence set forth in SEQ ID NO: 164. The nucleic acid molecule targeting variant BRAFp.V600Emay comprise a first strand having a sequence set forth in SEQ ID NO: 15, and a second strand having a sequence set forth in SEQ ID NO: 16. The nucleic acid molecule targeting variant BRAFp.V600Emay comprise a first strand having a sequence set forth in SEQ ID NO: 169, and a second strand having a sequence set forth in SEQ ID NO: 170. The nucleic acid molecule targeting variant NRASQ61K(for example, NRASc.181C>A p.Q61K) may comprise a first strand having a sequence set forth in SEQ ID NO: 71, and a second strand having a sequence set forth in SEQ ID NO: 72. The nucleic acid molecule targeting variant NRASQ61K(for example, NRASc.181C>A p.Q61K) may comprise a first strand having a sequence set forth in SEQ ID NO: 39, and a second strand having a sequence set forth in SEQ ID NO: 40. The nucleic acid molecule targeting variant KRASc.38G>A p.G13Dmay comprise a first strand having a sequence set forth in SEQ ID NO: 63, and a second strand having a sequence set forth in SEQ ID NO: 64. The nucleic acid molecule targeting variant KRASc.38G>A p.G13Dmay comprise a first strand having a sequence set forth in SEQ ID NO: 210, and a second strand having a sequence set forth in SEQ ID NO: 211. The nucleic acid molecule targeting variant CTNNB1c.133_135delTCT p.S45Delmay comprise a first strand having a sequence set forth in SEQ ID NO: 65, and a second strand having a sequence set forth in SEQ ID NO: 66. The nucleic acid molecule targeting variant CTNNB1c.133_135delTCT p.S45Delmay comprise a first strand having a sequence set forth in SEQ ID NO: 212, and a second strand having a sequence set forth in SEQ ID NO: 213. The nucleic acid molecule targeting variant GATA3c.1006dupG p.D336Gfs*17may comprise a first strand having a sequence set forth in SEQ ID NO: 67, and a second strand having a sequence set forth in SEQ ID NO: 68. The nucleic acid molecule targeting variant GATA3c.1006dupG p.D336Gfs*17may comprise a first strand having a sequence set forth in SEQ ID NO: 214, and a second strand having a sequence set forth in SEQ ID NO: 215. The nucleic acid molecule targeting variant NRASp.Q61R(for example, NRASc.182A>G p.Q61R) may comprise a first strand having a sequence set forth in SEQ ID NO: 69, and a second strand having a sequence set forth in SEQ ID NO: 70. The nucleic acid molecule targeting variant NRASQ61Rmay comprise a first strand having a sequence set forth in SEQ ID NO: 216, and a second strand having a sequence set forth in SEQ ID NO: 217. In another combination, the nucleic acid molecule targeting variant PIK3CA may comprise a first strand having a sequence set forth in SEQ ID NO: 5, and a second strand having a sequence set forth in SEQ ID NO: 6, the nucleic acid molecule targeting variant FBXW7 may comprise a first strand having a sequence set forth in SEQ ID NO: 7, and a second strand having a sequence set forth in SEQ ID NO: 8, and the nucleic acid molecule targeting variant APC may comprise a first strand having a sequence set forth in SEQ ID NO: 9, and a second strand having a sequence set forth in SEQ ID NO: 10. In another combination, the nucleic acid molecule targeting variant PIK3CA may comprise a first strand having a sequence set forth in SEQ ID NO: 159, and a second strand having a sequence set forth in SEQ ID NO: 160, the nucleic acid molecule targeting variant FBXW7 may comprise a first strand having a sequence set forth in SEQ ID NO: 161, and a second strand having a sequence set forth in SEQ ID NO: 162, and the nucleic acid molecule targeting variant APC may comprise a first strand having a sequence set forth in SEQ ID NO: 163, and a second strand having a sequence set forth in SEQ ID NO: 164. In another combination, the nucleic acid molecule targeting variant PIK3CA may comprise a first strand having a sequence set forth in SEQ ID NO: 1, and a second strand having a sequence set forth in SEQ ID NO: 2, and the nucleic acid molecule targeting variant FBXW7 may comprise a first strand having a sequence set forth in SEQ ID NO: 7, and a second strand having a sequence set forth in SEQ ID NO: 8. In another combination, the nucleic acid molecule targeting variant PIK3CA may comprise a first strand having a sequence set forth in SEQ ID NO: 155, and a second strand having a sequence set forth in SEQ ID NO: 156, and the nucleic acid molecule targeting variant FBXW7 may comprise a first strand having a sequence set forth in SEQ ID NO: 161, and a second strand having a sequence set forth in SEQ ID NO: 162. In another combination, the nucleic acid molecule targeting variant PIK3CA may comprise a first strand having a sequence set forth in SEQ ID NO: 5, and a second strand having a sequence set forth in SEQ ID NO: 6, and the nucleic acid molecule targeting variant FBXW7 may comprise a first strand having a sequence set forth in SEQ ID NO: 7, and a second strand having a sequence set forth in SEQ ID NO: 8. In another combination, the nucleic acid molecule targeting variant PIK3CA may comprise a first strand having a sequence set forth in SEQ ID NO: 159, and a second strand having a sequence set forth in SEQ ID NO: 160, and the nucleic acid molecule targeting variant FBXW7 may comprise a first strand having a sequence set forth in SEQ ID NO: 161, and a second strand having a sequence set forth in SEQ ID NO: 162. In another combination, the nucleic acid molecule targeting variant PIK3CA may comprise a first strand having a sequence set forth in SEQ ID NO: 1, and a second strand having a sequence set forth in SEQ ID NO: 2, and the nucleic acid molecule targeting variant APC may comprise a first strand having a sequence set forth in SEQ ID NO: 9, and a second strand having a sequence set forth in SEQ ID NO: 10. In another combination, the nucleic acid molecule targeting variant PIK3CA may comprise a first strand having a sequence set forth in SEQ ID NO: 155, and a second strand having a sequence set forth in SEQ ID NO: 156, and the nucleic acid molecule targeting variant APC may comprise a first strand having a sequence set forth in SEQ ID NO: 163, and a second strand having a sequence set forth in SEQ ID NO: 164. In another combination, the nucleic acid molecule targeting variant PIK3CA may comprise a first strand having a sequence set forth in SEQ ID NO: 5, and a second strand having a sequence set forth in SEQ ID NO: 6, and the nucleic acid molecule targeting variant APC may comprise a first strand having a sequence set forth in SEQ ID NO: 9, and a second strand having a sequence set forth in SEQ ID NO: 10. In another combination, the nucleic acid molecule targeting variant PIK3CA may comprise a first strand having a sequence set forth in SEQ ID NO: 159, and a second strand having a sequence set forth in SEQ ID NO: 160, and the nucleic acid molecule targeting variant APC may comprise a first strand having a sequence set forth in SEQ ID NO: 163, and a second strand having a sequence set forth in SEQ ID NO: 164. In another combination, the nucleic acid molecule targeting FBXW7 may comprise a first strand having a sequence set forth in SEQ ID NO: 7, and a second strand having a sequence set forth in SEQ ID NO: 8, and the nucleic acid molecule targeting variant APC may comprise a first strand having a sequence set forth in SEQ ID NO: 9, and a second strand having a sequence set forth in SEQ ID NO: 10. In another combination, the nucleic acid molecule targeting FBXW7 may comprise a first strand having a sequence set forth in SEQ ID NO: 161, and a second strand having a sequence set forth in SEQ ID NO: 162, and the nucleic acid molecule targeting variant APC may comprise a first strand having a sequence set forth in SEQ ID NO: 163, and a second strand having a sequence set forth in SEQ ID NO: 164. In another combination, the nucleic acid molecule targeting NRAS may comprise a first strand having a sequence set forth in SEQ ID NO: 72, and a second strand having a sequence set forth in SEQ ID NO: 71. In another combination, the nucleic acid molecule targeting NRAS may comprise a first strand having a sequence set forth in SEQ ID NO: 39, and a second strand having a sequence set forth in SEQ ID NO: 40. In another combination, the nucleic acid molecule targeting PIK3CA1 (PIK3CAc.3140A>G p.H1047R) may comprise a first strand having a sequence set forth in SEQ ID NO: 5, and a second strand having a sequence set forth in SEQ ID NO: 6, and the nucleic acid molecule targeting variant FBXW7 may comprise a first strand having a sequence set forth in SEQ ID NO: 7, and a second strand having a sequence set forth in SEQ ID NO: 8. In another combination, the nucleic acid molecule targeting PIK3CA1 (PIK3CAc.3140A>G p.H1047R) may comprise a first strand having a sequence set forth in SEQ ID NO: 159, and a second strand having a sequence set forth in SEQ ID NO: 160, and the nucleic acid molecule targeting variant FBXW7 may comprise a first strand having a sequence set forth in SEQ ID NO: 161, and a second strand having a sequence set forth in SEQ ID NO: 162. In another combination, the nucleic acid molecule targeting PIK3CA2 (PIK3CAc.1633G>A p.E545K) may comprise a first strand having a sequence set forth in SEQ ID NO: 1, and a second strand having a sequence set forth in SEQ ID NO: 2, and the nucleic acid molecule targeting variant GATA3 may comprise a first strand having a sequence set forth in SEQ ID NO: 67, and a second strand having a sequence set forth in SEQ ID NO: 68. In another combination, the nucleic acid molecule targeting PIK3CA2 (PIK3CAc.1633G>A p.E545K) may comprise a first strand having a sequence set forth in SEQ ID NO: 155, and a second strand having a sequence set forth in SEQ ID NO: 156, and the nucleic acid molecule targeting variant GATA3 may comprise a first strand having a sequence set forth in SEQ ID NO: 214, and a second strand having a sequence set forth in SEQ ID NO: 215. In another combination, the nucleic acid molecule targeting PIK3CA1 (PIK3CAc.3140A>G p.H1047R) may comprise a first strand having a sequence set forth in SEQ ID NO: 5, and a second strand having a sequence set forth in SEQ ID NO: 6, the nucleic acid molecule targeting variant FBXW7 may comprise a first strand having a sequence set forth in SEQ ID NO: 7, and a second strand having a sequence set forth in SEQ ID NO: 8, and the nucleic acid molecule targeting variant APC may comprise a first strand having a sequence set forth in SEQ ID NO: 9, and a second strand having a sequence set forth in SEQ ID NO: 10. In another combination, the nucleic acid molecule targeting PIK3CA1 (PIK3CAc.3140A>G p.H1047R) may comprise a first strand having a sequence set forth in SEQ ID NO: 159, and a second strand having a sequence set forth in SEQ ID NO: 160, the nucleic acid molecule targeting variant FBXW7 may comprise a first strand having a sequence set forth in SEQ ID NO: 161, and a second strand having a sequence set forth in SEQ ID NO: 162, and the nucleic acid molecule targeting variant APC may comprise a first strand having a sequence set forth in SEQ ID NO: 163, and a second strand having a sequence set forth in SEQ ID NO: 164. In another combination, the nucleic acid molecule targeting PIK3CAc.3140A>G p.H1047Rmay comprise a first strand having a sequence set forth in SEQ ID NO: 5, and a second strand having a sequence set forth in SEQ ID NO: 6, and the nucleic acid molecule targeting variant KRASc.38G>A p.G13Dmay comprise a first strand having a sequence set forth in SEQ ID NO: 63, and a second strand having a sequence set forth in SEQ ID NO: 64. In another combination, the nucleic acid molecule targeting PIK3CAc.3140A>G p.H1047Rmay comprise a first strand having a sequence set forth in SEQ ID NO: 159, and a second strand having a sequence set forth in SEQ ID NO: 160, and the nucleic acid molecule targeting variant KRASc.38G>A p.G13Dmay comprise a first strand having a sequence set forth in SEQ ID NO: 210, and a second strand having a sequence set forth in SEQ ID NO: 211. In another combination, the nucleic acid molecule targeting PIK3CAc.3140A>G p.H1047Rmay comprise a first strand having a sequence set forth in SEQ ID NO: 5, and a second strand having a sequence set forth in SEQ ID NO: 6, the nucleic acid molecule targeting variant KRASc.38G>A p.G13Dmay comprise a first strand having a sequence set forth in SEQ ID NO: 63, and a second strand having a sequence set forth in SEQ ID NO: 64, and the nucleic acid molecule targeting variant CTNNB1c.133_135delTCT p.S45Delmay comprise a first strand having a sequence set forth in SEQ ID NO: 65, and a second strand having a sequence set forth in SEQ ID NO: 66. In another combination, the nucleic acid molecule targeting PIK3CAc.3140A>G p.H1047Rmay comprise a first strand having a sequence set forth in SEQ ID NO: 159, and a second strand having a sequence set forth in SEQ ID NO: 160, the nucleic acid molecule targeting variant KRASc.38G>A p.G13Dmay comprise a first strand having a sequence set forth in SEQ ID NO: 210, and a second strand having a sequence set forth in SEQ ID NO: 211, and the nucleic acid molecule targeting variant CTNNB1c.133_135delTCT p.S45Delmay comprise a first strand having a sequence set forth in SEQ ID NO: 212, and a second strand having a sequence set forth in SEQ ID NO: 213. In another combination, the nucleic acid molecule targeting PIK3CAc.3140A>G p.H1047Rmay comprise a first strand having a sequence set forth in SEQ ID NO: 5, and a second strand having a sequence set forth in SEQ ID NO: 6, and the nucleic acid molecule targeting variant FBXW7c.1514G>T p.R505Lmay comprise a first strand having a sequence set forth in SEQ ID NO: 7, and a second strand having a sequence set forth in SEQ ID NO: 8. In another combination, the nucleic acid molecule targeting PIK3CAc.3140A>G p.H1047Rmay comprise a first strand having a sequence set forth in SEQ ID NO: 159, and a second strand having a sequence set forth in SEQ ID NO: 160, and the nucleic acid molecule targeting variant FBXW7c.1514G>T p.R505Lmay comprise a first strand having a sequence set forth in SEQ ID NO: 161, and a second strand having a sequence set forth in SEQ ID NO: 162. In another combination, the nucleic acid molecule targeting PIK3CAc.3140A>G p.H1047Rmay comprise a first strand having a sequence set forth in SEQ ID NO: 5, and a second strand having a sequence set forth in SEQ ID NO: 6, the nucleic acid molecule targeting variant FBXW7c.1514G>T p.R505Lmay comprise a first strand having a sequence set forth in SEQ ID NO: 7, and a second strand having a sequence set forth in SEQ ID NO: 8, and the nucleic acid molecule targeting variant APCc.4666del p.T1556fsmay comprise a first strand having a sequence set forth in SEQ ID NO: 9, and a second strand having a sequence set forth in SEQ ID NO: 10. In another combination, the nucleic acid molecule targeting PIK3CAc.3140A>G p.H1047Rmay comprise a first strand having a sequence set forth in SEQ ID NO: 159, and a second strand having a sequence set forth in SEQ ID NO: 160, the nucleic acid molecule targeting variant FBXW7c.1514G>T p.R505Lmay comprise a first strand having a sequence set forth in SEQ ID NO: 161, and a second strand having a sequence set forth in SEQ ID NO: 162, and the nucleic acid molecule targeting variant APCc.4666del p.T1556fsmay comprise a first strand having a sequence set forth in SEQ ID NO: 163, and a second strand having a sequence set forth in SEQ ID NO: 164. In another combination, the nucleic acid molecule targeting PIK3CAc.1633G>A p.E545Kmay comprise a first strand having a sequence set forth in SEQ ID NO: 1, and a second strand having a sequence set forth in SEQ ID NO: 2, and the nucleic acid molecule targeting variant GATA3c.1006dupG p.D336Gfs*17may comprise a first strand having a sequence set forth in SEQ ID NO: 67, and a second strand having a sequence set forth in SEQ ID NO: 68. In another combination, the nucleic acid molecule targeting PIK3CAc.1633G>A p.E545Kmay comprise a first strand having a sequence set forth in SEQ ID NO: 155, and a second strand having a sequence set forth in SEQ ID NO: 156, and the nucleic acid molecule targeting variant GATA3c.1006dupG p.D336Gfs*17may comprise a first strand having a sequence set forth in SEQ ID NO: 214, and a second strand having a sequence set forth in SEQ ID NO: 215. In another combination, the nucleic acid molecule targeting PIK3CAc.1633G>A p.E545Kmay comprise a first strand having a sequence set forth in SEQ ID NO: 155, and a second strand having a sequence set forth in SEQ ID NO: 156 and the nucleic acid molecule targeting variant GATA3c.1006dupG p.D336Gfs*17may comprise a first strand having a sequence set forth in SEQ ID NO: 214, and a second strand having a sequence set forth in SEQ ID NO: 215. In another combination, the nucleic acid molecule targeting NRASQ61K(for example, NRASc.181C>Ap.Q61K) may comprise a first strand having a sequence set forth in SEQ ID NO: 71, and a second strand having a sequence set forth in SEQ ID NO: 72, the nucleic acid molecule targeting variant NRASp.Q61R(for example, NRASc.182A>G p.Q61R) may comprise a first strand having a sequence set forth in SEQ ID NO: 69, and a second strand having a sequence set forth in SEQ ID NO: 70, and the nucleic acid molecule targeting variant BRAFp.V600Emay comprise a first strand having a sequence set forth in SEQ ID NO: 15, and a second strand having a sequence set forth in SEQ ID NO: 16. In another combination, the nucleic acid molecule targeting NRASQ61K(for example, NRASc.181C>A p.Q61K) may comprise a first strand having a sequence set forth in SEQ ID NO: 39, and a second strand having a sequence set forth in SEQ ID NO: 40, the nucleic acid molecule targeting variant NRASp.Q61R(for example, NRASc.182A>G p.Q61R) may comprise a first strand having a sequence set forth in SEQ ID NO: 216, and a second strand having a sequence set forth in SEQ ID NO: 217, and the nucleic acid molecule targeting variant BRAFp.V600Emay comprise a first strand having a sequence set forth in SEQ ID NO: 169, and a second strand having a sequence set forth in SEQ ID NO: 170. A nucleic acid molecule targeting variant NRAS may comprise a first strand having a sequence set forth in SEQ ID NO: 39, and a second strand having a sequence set forth in SEQ ID NO: 40 (together referred to as siRNA8). A nucleic acid molecule targeting variant NRAS may comprise a first strand having a sequence set forth in SEQ ID NO: 71, and a second strand having a sequence set forth in SEQ ID NO: 72 (together referred to as siRNA8). The first and / or second strands may optionally comprise a TT motif, preferably at a 5’ end. Other nucleic acid molecules targeting variant NRAS may comprise one (or more if double stranded) of the sequences set forth in SEQ ID NOs: 25-62. Any of SEQ ID NOs: 25-62 may optionally comprise a TT motif, for example at a 5’ or 3’ end. The nucleic acid molecules, compositions, combinations and pharmaceutical compositions described herein can be administered by different routes, including orally, parenterally, sublingually, intradermally, transdermally, rectally, transmucosally, topically, via inhalation, via buccal administration, intrapleurally, intravenously, intraarterially, intraperitoneally, subcutaneously, intramuscularly, intranasally, intrathecally, and / or intraarticularly, or combinations thereof. In some embodiments the nucleic acid molecules are administered orally. In some embodiments the nucleic acid molecules are administered intravenously. In some embodiments the nucleic acid molecules are administered topically. In some embodiments the nucleic acid molecules are administered via microneedle injection. In some embodiments the nucleic acid molecules are administered via microneedle injection into the dermis. The nucleic acid molecules may be administered intradermally. It will be appreciated that it is not necessary for all the nucleic acid molecules to be administered in the same way, for example where the first and second nucleic acid molecules are formulated in separate compositions, the first nucleic acid molecule may be administered in one way, and the second nucleic acid molecule may be administered in a different way. One or more of the nucleic acid molecules may be formulated for delivery as a lipid nanoparticle, a liposome, an exosome, a polymeric nanoparticle, an inorganic nanoparticle, a receptor-targeted nanoparticle, a receptor-targeted lipid nanoparticle or a ruxolitinib and thalidomide co-delivered polyelectrolyte nanocomplex (RTNP). One or more of the nucleic acid molecules may be formulated for delivery as a lipid nanoparticle. One or more of the nucleic acid molecules may be formulated for delivery as a receptor-targeted lipid nanoparticle. One or more of the nucleic acid molecules may be encapsulated within a lipid nanoparticle or a receptor-targeted lipid nanoparticle. Also described herein is a lipid nanoparticle or lipid nanoparticle composition comprising a nucleic acid molecule or combination of nucleic acid molecules as described herein. Compositions and combinations as described herein may comprise at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten nucleic acid molecules. A composition or combination as described herein may comprise at least three nucleic acid molecules. A composition or combination as described herein may comprise at least four nucleic acid molecules. A composition or combination as described herein may comprise at least five nucleic acid molecules. Also provided herein is a composition or combination as described herein for use in a method of inducing apoptosis in a tumour of a subject. Also provided herein is a composition or combination as described herein for use in a method of suppressing growth of a tumour of a subject. Also provided herein is a composition or combination as described herein for use in a method of treating cancer in a subject. The method may comprise (a) identifying at least two pathogenic genomic sequence variants relevant to the tumour and / or cancer of the subject, wherein the first nucleic acid molecule comprises a sequence that is complementary to an mRNA of a pathogenic genomic sequence variant identified in step (a), and wherein each further nucleic acid comprise a sequence that is complementary to an mRNA of a different pathogenic genomic sequence variant identified in step (a), and administering the composition or combination to the subject. The method may comprise genotyping the subject’s tumour or a sample of the subject’s tumour. The method may comprise sequencing a cell free RNA sample or a cell free DNA sample from the subject. The sequencing may be ultra-deep sequencing or massively parallel sequencing-by-synthesis. Step (a) may comprise predicting at least one pathogenic genomic sequence variant expressed in the tumour and / or cancer of the subject based on known pathogenic genomic sequence variant for the same or similar tumour and / or cancer types. The method may comprise administering the at least two nucleic acid molecules separately. The method may comprise administering the at least two nucleic acid molecules sequentially in any order. The method may comprise administering the at least two nucleic acid molecules simultaneously. Advantageously and surprisingly, the dose of each nucleic acid molecule administered to a subject may be lower (e.g.50% less) compared to a dose that would be used if only one nucleic acid molecule were to be administered. In any of the methods, compositions and combinations described herein, the subject may be a mammalian subject. The subject may be a human subject. In any of the methods, compositions and combinations described herein, the at least two nucleic acid molecules may inhibit or reduce proliferation of tumour cells. A nucleic acid molecule and a target mRNA are complementary to each other when a sufficient number of nucleobases of the nucleic acid molecule can hydrogen bond with the corresponding nucleobases of the target mRNA, such that a desired effect (for example inhibition of target gene expression) will occur. Non-complementary nucleobases between a nucleic acid molecule and a target mRNA may be tolerated provided that the nucleic acid molecule remains able to specifically hybridize to a target mRNA. Moreover, a nucleic acid molecule may hybridize over one or more segments of a mRNA such that intervening or adjacent segments are not involved in the hybridization event (e.g., a loop structure, mismatch or hairpin structure). In certain embodiments, the nucleic acid molecules provided herein, or a specified portion thereof, are, or are at least, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%), or 100% complementary to a target mRNA, a target region, target segment, or specified portion thereof. In some cases, a first nucleic acid molecule may be at least 90% complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject. A second nucleic acid molecule may be at least 90% complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject. In some cases, a first nucleic acid molecule may be at least 95% complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject. A second nucleic acid molecule may be at least 95% complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject. In some cases, a first nucleic acid molecule may be at least 98% complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject. A second nucleic acid molecule may be at least 98% complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject. In some cases, a first nucleic acid molecule may be at least 99% complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject. A second nucleic acid molecule may be at least 99% complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject. Percent complementarity of a nucleic acid molecule with a target mRNA to be determined using routine methods. For example, a nucleic acid molecule in which 18 of 20 nucleobases of the nucleic acid molecule are complementary to a target mRNA, and would therefore specifically hybridize, would represent 90 percent complementarity. In this example, the remaining noncomplementary nucleobases may be clustered or interspersed with complementary nucleobases and need not be contiguous to each other or to complementary nucleobases. Percent complementarity of a nucleic acid molecule with a region of a target mRNA can be determined routinely using BLAST programs (basic local alignment search tools) known in the art. Percent homology, sequence identity or complementarity, can be determined by, for example, the Gap program using default settings. Any of the nucleic acid molecules described herein may comprise one or more chemical modifications. Chemical modifications include modifications of the nucleobase, modifications of the sugar moiety and modified internucleoside linkages. Such chemical modifications may be included to improve the stability of the nucleic acid molecule, and / or improve its resistance to degradation once administered. Suitable strategies for chemically modifying nucleic acid molecules to facilitate therapeutic delivery are known in the art. The nucleic acid molecules described herein may comprise any number of chemical modifications, in any combination. Where the nucleic acid molecules are double stranded, such as in the case of siRNAs, one or both of the strands may comprise chemically modified nucleotides. Any of the nucleic acid molecules described herein may comprise one or more sugar modifications as a chemical modification. These include a modified version of the ribosyl moiety, such as 2’-O-modified RNA such as 2’-O-alkyl or 2’-O-(substituted)alkyl e.g. 2’-O-methyl, 2’-O-(2- cyanoethyl), 2’-O-(2- methoxy)ethyl (2’-MOE), 2’-O-(2-thiomethyl)ethyl, 2’-O-butyryl, 2’-O-propargyl, 2’-O-allyl, 2’-O-(3- amino)propyl, 2’-O-(3-(dimethylamino)propyl), 2’-O-(2-amino)ethyl, 2’-O-(2-(dimethylamino)ethyl); 2’- deoxy (DNA); 2’- O-(haloalkoxy)methyl (Arai K. et al. Bioorg. Med. Chem.2011, 21, 6285) e.g.2’-O-(2- chloroethoxy)methyl (MCEM), 2’- O-(2, 2-dichloroethoxy)methyl (DCEM); 2’-O- alkoxycarbonyl e.g.2’- O-[2-(methoxycarbonyl)ethyl] (MOCE), 2’-O-[2-(N- methylcarbamoyl)ethyl] (MCE), 2’-O-[2-(N,N- dimethylcarbamoyl)ethyl] (DCME); 2’-halo e.g. 2’-F, FANA (2’-F arabinosyl nucleic acid); carbasugar and azasugar modifications; 3’-O-alkyl e.g. 3’-O-methyl, 3’-O-butyryl, 3’-0-propargyl; and their derivatives. Other sugar modifications include "bridged" or "bicylic" nucleic acid (BNA), e.g. locked nucleic acid (LNA), xylo-LNA, α-L-LNA, β-D-LNA, cEt (2’-O,4’-C constrained ethyl) LNA, cMOEt (2’-O,4’- C constrained ethoxyethyl) LNA, ethylene-bridged nucleic acid (ENA), tricyclo DNA; unlocked nucleic acid (UNA); cyclohexenyl nucleic acid (CeNA), altriol nucleic acid (ANA), hexitol nucleic acid (HNA), fluorinated HNA (F-HNA), pyranosyl-RNA (p-RNA), 3’-deoxypyran- osyl-DNA (p-DNA); morpholino (as e.g. in PMO, PPMO, PMOPlus, PMO-X); and their derivatives. In particular, the sugar modification may be selected from the group consisting of 2’-Fluoro (2’-F), 2’-O-methyl (2’-OMe), 2’-O-methoxyethyl (2’- MOE), and 2’-amino. Any of the nucleic acid molecules described herein may comprise one or more nucleobase modifications as a chemical modification. These include modified versions of the natural purine and pyrimidine bases (e.g. adenine, uracil, guanine, cytosine, and thymine), such as inosine, hypoxanthine, orotic acid, agmatidine, lysidine, 2-thiopyrimidine (e.g.2-thiouracil, 2-thiothymine), G-clamp and its derivatives, 5- substituted pyrimidine (e.g. 5-methylcytosine, 5-methyluracil, 5-halouracil, 5-propynyluracil, 5- propynylcytosine, 5-aminomethyluracil, 5-hydroxymethyluracil, 5-aminomethylcytosine, 5- hydroxymethylcytosine, Super T), 2,6-di-aminopurine, 7-deazaguanine, 7-deazaadenine, 7-aza-2, 6- diaminopurine, 8-aza-7-deazaguanine, 8-aza-7-deazaadenine, 8-aza-7-deaza-2, 6-diaminopurine, Super G, Super A, and N4-ethylcytosine, or derivatives thereof; N2 -cyclopentyl-guanine (cPent-G), N2 -cyclopentyl-2-aminopurine (cPent-AP), and N2 -propyl-2-aminopurine (Pr-AP), or derivatives thereof; and degenerate or universal bases, like 2, 6-difluorotoluene or absent bases like abasic sites (e.g.1- deoxyribose, 1,2-dideoxyribose, 1-deoxy-2-O- methylribose; or pyrrolidine derivatives in which the ring oxygen has been replaced with nitrogen (azaribose)). Any of the nucleic acid molecules described herein may comprise one or more modified internucleoside linkages (also referred to as backbone modifications). These include modified versions of the phosphodiester present in RNA, such as phosphorothioate (PS), phosphorodithioate (PS2), phosphonoacetate (PACE), phosphonoacetamide (PACA), thiophosphonoacetate, thiophosphonoacetamide, phosphorothioate prodrug, H-phosphonate, methyl phosphonate, methyl phosphonothioate, methyl phosphate, methyl phosphorothioate, ethyl phosphate, ethyl phosphorothioate, boranophosphate, boranophosphorothioate, methyl boranophosphate, methyl boranophosphorothioate, methyl boranophosphonate, methylboranophosphonothioate, and their derivatives. Another modification includes phosphoramidite, phosphoramidate, N3’→P5’ phosphoramidate, phosphordiamidate, phosphorothiodiamidate, sulfamate, dimethylenesulfoxide, sulfonate, triazole, oxalyl, carbamate, methyleneimino (MMI), and thioacetamido nucleic acid (TANA); and their derivatives. Aspects and embodiments described herein with the term “comprising” may include other features or steps within the scope. It is also understood that aspects and embodiments described as “comprising” also describes aspect and embodiments wherein the term “comprising” is replaced by the term “consisting essentially of” or “consisting of”. The phrase "selected from the group comprising" may be substituted with the phrase "selected from the group consisting of" and vice versa, wherever they occur herein. It is also understood that the application discloses all combinations of any of the above aspects and embodiments described above with each other, unless the context demands otherwise. Similarly, the application discloses all combinations of the preferred and / or optional features either singly or together with any of the other aspects, unless the context demands otherwise. The invention will now be further described by way of the following Examples, which are meant to serve to assist one of ordinary skill in the art in carrying out the invention and are not intended in any way to limit the scope of the invention, with reference to the Figures. EXAMPLES Example 1 A single dose of variant-allele-specific single target siRNA induces knockdown in a benign variant KRAS-driven endothelial cell model of arteriovenous malformations in vitro and triggers apoptosis. Figure 1 shows the effects of the siRNA siKRASG12V on confluency and apoptosis in HUVEC wild- type and mutant clones (B1 and C1). As can be seen from the Figure, the siRNA induces apoptosis (indicated by increased caspase 3 / 7 activity) and cell death (indicated by reduced confluency). Example 2 - Variant-specific knockdown of oncogenic variants in dysplastic tumour disease A single dose of variant-allele-specific single target siRNA induces knockdown in dysplastic variant NRAS-driven leptomeningeal melanocytic disease in vitro and triggers apoptosis. Leptomeningeal melanocytosis is a dysplastic disease which develops in a minority of patients with CMN syndrome and usually progresses to fatal melanoma, despite some benefit from treatment with MEKi trametinib pioneered by our team(11). Leptomeningeal biopsies from one patient underwent diagnostic sequencing confirming the presence of NRASc.181C>A p.Q61Kand in addition a single whole chromosomal aberration as previously described in association with dysplastic progression(14, 15). Treatment of dysplastic leptomeningeal melanocytic cells grown in culture with a single dose of siNRASc.181C>A p.Q61Kinduced apoptosis in this patient sample in contrast to no induction of apoptosis by trametinib (T1) (Figure 2). Example 3 - Variant-specific knockdown of hot-spot oncogenic variants in cancer cell lines High depth sequencing and low allele frequency pipeline in a range of cancer cell lines confirms the known driver pathogenic variants in cell line databases, and identifies more recognised oncogenic variants. All known pathogenic variants described in cell line databases (as defined in methods) were detected by our sequencing and pipeline / filters. In addition however, addition substantial numbers of pathogenic variants were detected and confirmed on manual inspection of the bam files to be real (table 1, column Yes). These variants were generally at lower variant allele frequencies and therefore would often not be reported using lower depth sequencing methods or less sensitive pipelines / filters. These variants could be those which are in subclones of the tumour cell lines and which could be important in a clinical setting as those which would have a mutational profile that may be different / additional to the main clone(s) – in other words subclones which could lead to treatment resistance, recurrence or metastasis. Results are shown in Figure 3, which shows from left to right: Total number of variants detected using the pipeline in each of the cell lines, Total number of variants after the application of filters, Total number of variants confirmed as convincing by manual individual inspection of the sequence and which were not reported in any online databases related to the cell lines. All established oncogenic variants tested so far in multiple cancer cell line types are amenable to allele-specific siRNA design (Figures 4-10). Figure 4 shows RT-qPCR data of RNA levels following siRNA knockdown of hotspot mutations in SKOV3 cell line. The siRNAs tested can preferentially target pathogenic genomic sequence variants. Figure 5 shows RT-qPCR data of RNA levels following siRNA knockdown of hotspot mutations in MCF-7 cell line. The siRNAs tested can preferentially target pathogenic genomic sequence variants. Example 4 - MaGiC combinations of siRNAs knockdown all components at least as well as the single siRNAs, despite the combinations being half doses of the single siRNAs As shown in Figure 6, MaGiC combination of siRNAs were able to knock down each of PIK3CA, FBXW7 and APC in the SKOV3 cell line (Fig 6B and 6C). The extent of knockdown of each variant was at least as good (if not better) than that achievable with single siRNAs (Fig 6A), and this was achieved despite the doses of each siRNA present in MaGiC being a third of the dose of the single siRNAs (since there are 3 siRNAs in this MaGiC combination, the doses used of each are a third of the dose if only one siRNA was to be administered). Figure 7 similarly shows knockdown of the target variants NRAS and MYC in the H1299 cell line by MaGiC (siNRAS+siMYC) (Fig 7B and 7C) compared to single siRNAs (Fig 7A). Again the extent of target knockdown is comparable between MaGiC and single siRNA, despite the lower doses of each siRNA in MaGiC (half the single siRNA dose for each of siNRAS and siMYC). Accordingly, despite each siRNA being present in MaGiC combinations at half or a third of the dose of single siRNA treatment, the MaGiC approach provides surprisingly effective knockdown of target pathogenic variants. Thus, MaGiC provides a therapeutic tool which is as effective as single siRNAs, with potential to minimise side effects and / or toxicity as a result. Example 5 - Double target variant-allele-specific MaGiC (“MaGiC2”) inhibits proliferation and induces apoptosis in ovarian cancer and breast cancer cell lines which have at least two oncogenic variants, more effectively than either single siRNA alone At least one single targeted siRNA against a specific oncogene in each cell line slows proliferation or causes growth arrest, but it would not have been possible to guess which in advance from sequencing data (Figure 11 a and b). In some cases one of the single siRNAs was more effective at reducing proliferation and another was more effective at inducing apoptosis, whereas the combination did both (Figure 11a). Even where these effects were not significantly more than the best single siRNA this combination is therefore more effective as a whole than either alone. Example 6 - A single dose of variant-allele-specific double target MaGiC (“MaGiC2”) induces apoptosis in an ovarian cancer cell line in vitro, and is more effective than a double MaGiC designed for a different cell line High depth diagnostic panel sequencing and bioinformatics pipeline analysis of ten cancer cell lines of different types of tumour confirmed the presence of database driver variants for those lines, and identified others at lower variant allele frequencies. SiRNAs were then designed against each of the DNA variants. When combining two siRNAs half the concentration of each was used, when using three it was a third. Giving a second dose of the double MaGiC therapy (to ensure delivery of the same amount of each as for a single siRNA) did not increase knockdown in vitro (Figure 6, Figure 7) and this was therefore not required. Treatment of ovarian cancer line SKOV3 with siRNAs targeted at the two highest allele load DNA variants resulted in suppression of proliferation and induction of apoptosis (orange curves), and this was more effective than either scrambled control (no significant effect) or treatment with a double target MaGiC therapy designed for a breast cancer line (Fig.11). There was also some effectiveness of the breast cancer line MaGiC on the ovarian line (green curves) (Fig.11), which could be due to the commonality of PIK3CA driver variants (although they are different variants in the two cell lines). Example 7 - A single dose of variant-allele-specific triple target MaGiC induce apoptosis in an ovarian cancer cell lines in vitro more effectively than double target MaGiC (“MaGiC2”) Treatment of ovarian cancer line SKOV3 with siRNAs targeted at the three highest allele load DNA variants (red curves) resulted in suppression of proliferation and induction of apoptosis more effectively than targeting two (Fig.12). This was particularly interesting as the third target was an APC heterozygous short indel, which would have been predicted in silico to be a loss of function variant. This data therefore suggests that siRNA knockdown of at least some pathogenic LOF variants (i.e. loss of tumour suppressor rather than oncogenic gain) may be effective. Example 8 - Variant-allele-targeted siRNA are synergistic with existing pathway inhibitors The inventors first demonstrated this in the context of benign tumours, where Trametinib (MEKi) could reduce proliferation in cultured oncogenic-NRAS-variant congenital melanocytic naevus cells but did not induce any apoptosis when used alone (Figure 13). The allele-specific siRNA against the oncogenic NRAS variant inhibited proliferation and induced apoptosis, and a combination of the siRNA and Trametinib induced more apoptosis than the siRNA alone. Summary In conclusion the inventors have demonstrated that knockdown of single oncogenes in benign tumour cells induces apoptosis, and that knockdown can be achieved in vivo in an animal model using lipid nanoparticles which are compatible with human administration. Targeting of multiple oncogenes in cancer cell lines with a single dose of combined siRNAs can induce apoptosis in cell lines from different cancer types over the subsequent 2-7 day period. Targeting two oncogenes mutated in that cancer line is more effective than targeting two other random oncogenes, and targeting three is more effective than targeting two. Variant allele specificity increases effectiveness of apoptosis induction in cancer cell lines homozygous / hemizygous for that variant, and would be predicted to have fewer off target effects both at RNA and tissue level. Materials & Methods High depth sequencing of cancer cell lines Cell culture and DNA extraction: Cell lines were initially thawed and grown in vitro by the Cell Services Facility, at The Francis Crick Institute. Immortalised cell lines were selected based on increasing the number of cancer types and which cell lines were readily available (Table 1). Cell lines were grown to confluency in T75 flasks, washed with PBS once and passaged using TrypLE Express (#12605-028, ThermoFisher). Cells were counted using a Countess II automated cell counter (#AMQAX1000, ThermoFisher) and normalised to a concentration of 107cells / ml. These pellets were washed with 4ml cold PBS and centrifuged 3 times in 15ml centrifuge tubes, then placed on ice. A blood and cell culture DNA mini kit (#13323, Qiagen) was used to extract high quality and high molecular weight DNA from the cell pellets using an anion-exchange purification method. The protocol followed was according to the manufacturer’s instructions. DNA concentration was determined using a Qubit 4 Fluorometer (ThermoFisher) and contaminants using a NanoDrop 2000c Spectrophotometer (ThermoFisher). Table 1: A list of cell lines and a description of their cancer types. A total of 10 cancer cell lines were selected. Cancer Type: Cell line:Invasive breast carcinoma MCF7Colon carcinoma HCT116Clear cell renal cell CAKI-1 carcinoma Pancreatic ductal PANC1 adenocarcinoma Ovarian serous SKOV3 cystadenocarcinoma Prostate carcinoma DU145Lung adenocarcinoma A549Lung large cell carcinoma H1299Amelanotic melanoma C32Hepatocellular carcinomaSK-HEP-1Cutaneous melanoma SK-MEL-28Library preparation: Two panels were used to identify oncogene variants. Ampliseq for Illumina Cancer HotSpot Panel v2 and AmpliSeq for Illumina Focus Panel, targeting 50 and 52 genes respectively (Table 3). Furthermore, the AmpliSeq Illumina Focus Panel includes fusions and copy-number variations along with hotspots. Protocols for each panel were followed according to the manufacturer’s instructions (AmpliSeq for Illumina Cancer HotSpot Panel v2 Reference Guide, 2019), apart from one exemption: SPRIselect bead-based reagent (Beckman Coulter) was used for the clean-up of libraries instead of AmpureXP beads, resulting in higher yields. AmpliSeq UD Indexes (24 Indexes, 24 Samples) (#20019104, Illumina) were used to identify amplicons. Amplicon library concentration was assessed using a Qubit 4 Fluorometer and quality using a High Sensitivity D1000 ScreenTape (#5067- 5584, Agilent) along with High Sensitivity D1000 reagents (#5067-5585, Agilent). Table 3: Genes covered on each of the two cancer panels used for cancer cell line sequencing. AmpliSeq for Illumina Cancer AmpliSeq for Illumina HotSpot Panel Focus PanelTotal Total50 52ABL1 ABL1AKT1 AKT1ALK AKT3APC ALKATM ARBRAF AXLCDH1 BRAFCDKN2A CCND1CSF1R CDK4CTNNB1 CDK6EGFR CTNNB1ERBB2 DDR2ERBB4 EGFREZH2 ERBB2FBXW7 ERBB3FGFR1 ERBB4FGFR2 ERGFGFR3 ESR1FLT3 ETV1GNA11 ETV4GNAQ ETV5GNAS FGFR1HNF1A FGFR2HRAS FGFR3IDH1 FGFR4IDH2 GNA11JAK2 GNAQJAK3 HRASKDR IDH1KIT IDH2KRAS JAK1MET JAK2MLH1 JAK3MPL KITNOTCH1 KRASNPM1 MAP2K1NRAS MAP2K2PDGFRA METPIK3CA MTORPTEN MYCPTPN11 MYCNRB1 NRASRET NTRK1SMAD4 NTRK2SMARCB1 NTRK3SMO PDGFRASRC PIK3CASTK11 PPARGTP53 RAF1VHL RETROS1 SMO Targeted panel sequencing and variant analysis: Targeted DNA (whole-exome) sequencing of libraries was performed by the Advanced Sequencing Facility at The Francis Crick Institute, in a NOVASeq 6000 (Illumina) generating an average read depth of at least 10 million reads per sample (paired-end 100bp). A total of 15 libraries were sequenced, 10 obtained from the Cancer Hotspot panel and 5 from the Focus panel (Table 4). Table 4: Number of reads obtained from each of the 10 cell lines and corresponding cancer panel used for the library preparation. Cell line Reads Panel A549 18604475 CancerHotspot CAKI-1 16307766 CancerHotspot DU145 13477657 CancerHotspot H1299 9301850 CancerHotspot H1299 15389006 Focus HCT116 17613615 CancerHotspot HCT116 16766586 Focus MCF7 30249322 CancerHotspot MCF7 17618313 Focus PANC1 13863185 CancerHotspot SK-HEP-1 34235993 CancerHotspot SK-HEP-1 12306709 Focus SK-MEL-28 13324321 CancerHotspot Skov3 16836772 CancerHotspot Skov3 15888268 Focus Resulting FASTQ files were processed to detect somatic variants (GRCh38 genome assembly) in tumor- only mode using Mutect2 (GATK4) by the nf-core sarek pipeline (3.3.2) with the following parameters: nextflow run nf-core / sarek \ --input --outdir --wes \ --intervals --tools --skip_tools markduplicates \ -profile crick \ -r ${PIPELINE_VERSION} Resulting vcf files containing variants were annotated and filtered in QIAGEN QCI Interpret Translational (version 9.2.1.20231012) to identify predicted deleterious variants. Those variants known or predicted to affect cancer with a call quality of at least 20.0, read depth of at least 500 and a minimum allele fraction of 2.0 were retained. The following variants were excluded: those observed with an allele frequency greater than or equal to 0.001% of the genomes in the 1000 genomes project OR greater than or equal to 0.001% of the NHLBI ESP exomes (All) OR greater than or equal to 0.001% of the AFC Frequency OR greater than or equal to 0.001% of the ExAC Frequency OR greater than or equal to 0.001% of the gnomAD Maximum Frequency unless established Pathogenic common variant. From those variants identified as predicted deleterious, we initially selected those heterozygous with an allele frequency of at least 3%. Finally, variants were visually inspected using IGV (2.16.2) and those confirmed were selected for further experiments. siRNA design and knockdown testing siRNA design: The siRNAs were designed complementary to the variant sequence. The cDNA sequence surrounding the mutation of interest was obtained from Ensembl. Using a walk design, 18 19bp-long siRNA sequences were designed across the 37 bases surrounding the mutant nucleotide. Based upon results from previous siRNA design development in the laboratory, the central 6 siRNAs were tested for mutant allele-specific knockdown. The siRNAs were designed with a deoxythymidine dinucleotide (dTdT) overhang to increase stability. However, any siRNA described herein may be present with or without a deoxythymidine dinucleotide (dTdT) overhang. siRNA transfection: Forward transfection was performed to test expression knockdown using the designed siRNA.24 hours prior to transfection, 150,000 cells per well were seeded in 6 well plates. The cells were transfected with siRNA at 37.5nM using 5µl lipofectamine RNAi MAX (Thermo Fisher) in a total volume of 2ml complete media. When transfecting with the MaGiC siRNA combination, the concentration of each siRNA was divided by the number of siRNA in the mix, making the total siRNA concentration 37.5nM, consistent with single siRNA experiments. RNA was collected 48 hours post- transfection. For repeated transfections, cells were transfected at 24 hours post initial transfection with the same concentrations of siRNA as the first transfection. To control for the transfection reagent, lipofectamine RNAi MAX alone was added to the single transfected cells at 24 hours. siRNA sequences: siRNA sequences of the siRNAs which produced the highest variant-specific knockdown are summarised in the tables below. The sense and antisense sequences are described in combination as well as individually. Table 5 siRNA Sequence Sequence including 3’ [dT][dT]PIK3CA si4 (2) GAAAUCACUAAGCAGGAGA GAAAUCACUAAGCAGGAGA[dT][dT] (SEQ ID NO: 155) (SEQ ID NO: 1) PIK3CA si4 (2)_a UCUCCUGCUUAGUGAUUUC UCUCCUGCUUAGUGAUUUC[dT][dT] (SEQ ID NO: 156) (SEQ ID NO: 2) GATA3 si3 GCCAAUGGGGGACCCUGUC GCCAAUGGGGGACCCUGUC[dT][dT] (SEQ ID NO: 157) (SEQ ID NO: 3) GATA3 si3_a GACAGGGUCCCCCAUUGGC GACAGGGUCCCCCAUUGGC[dT][dT] (SEQ ID NO: 158) (SEQ ID NO: 4) PIK3CA si5 (1) UGAUGCACGUCAUGGUGGC UGAUGCACGUCAUGGUGGC[dT][dT] (SEQ ID NO: 159) (SEQ ID NO: 5) PIK3CA si5 (1)_a GCCACCAUGACGUGCAUCA GCCACCAUGACGUGCAUCA[dT][dT] (SEQ ID NO: 160) (SEQ ID NO: 6) FBXW7 si4 CAGCAGUCCUCUGUGUUCA CAGCAGUCCUCUGUGUUCA[dT][dT] (SEQ ID NO: 161) (SEQ ID NO: 7) FBXW7 si4_as UGAACACAGAGGACUGCUG UGAACACAGAGGACUGCUG[dT][dT] (SEQ ID NO: 162) (SEQ ID NO: 8) APC si1 UUGAUUCUGAAAGGACCU UUGAUUCUGAAAGGACCU[dT][dT] (SEQ ID NO: 163) (SEQ ID NO: 9) APC si1_as AGGUCCUUUCAGAAUCAA AGGUCCUUUCAGAAUCAA[dT][dT] (SEQ ID NO: 164) (SEQ ID NO: 10) Table 6 siRNA Sequence Sequence including 3’ [dT][dT]BRAF_V600E_1 GUCUAGCUACAGAGAAAUC GUCUAGCUACAGAGAAAUC[dT][dT] (SEQ ID NO: 165) (SEQ ID NO: 11) BRAF_V600E_1_as GAUUUCUCUGUAGCUAGAC GAUUUCUCUGUAGCUAGAC[dT][dT] (SEQ ID NO: 166) (SEQ ID NO: 12) BRAF_V600E_2 UCUAGCUACAGAGAAAUCU UCUAGCUACAGAGAAAUCU[dT][dT] (SEQ ID NO: 167) (SEQ ID NO: 13) BRAF_V600E_2_as AGAUUUCUCUGUAGCUAGA AGAUUUCUCUGUAGCUAGA[dT][dT] (SEQ ID NO: 168) (SEQ ID NO: 14) BRAF_V600E_3 CUAGCUACAGAGAAAUCUC CUAGCUACAGAGAAAUCUC[dT][dT] (SEQ ID NO: 169) (SEQ ID NO: 15) BRAF_V600E_3_as GAGAUUUCUCUGUAGCUAG GAGAUUUCUCUGUAGCUAG[dT][dT] (SEQ ID NO: 170) (SEQ ID NO: 16) BRAF_V600E_4 UAGCUACAGAGAAAUCUCG UAGCUACAGAGAAAUCUCG[dT][dT] (SEQ ID NO: 171) (SEQ ID NO: 17) BRAF_V600E_4_as CGAGAUUUCUCUGUAGCUA CGAGAUUUCUCUGUAGCUA[dT][dT] (SEQ ID NO: 172) (SEQ ID NO: 18) BRAF_V600E_5 AGCUACAGAGAAAUCUCGA AGCUACAGAGAAAUCUCGA[dT][dT] (SEQ ID NO: 173) (SEQ ID NO: 19) BRAF_V600E_5_as UCGAGAUUUCUCUGUAGCU UCGAGAUUUCUCUGUAGCU[dT][dT] (SEQ ID NO: 174) (SEQ ID NO: 20) BRAF_V600E_6 GCUACAGAGAAAUCUCGAU GCUACAGAGAAAUCUCGAU[dT][dT] (SEQ ID NO: 175) (SEQ ID NO: 21) BRAF_V600E_6_as AUCGAGAUUUCUCUGUAGC AUCGAGAUUUCUCUGUAGC[dT][dT] (SEQ ID NO: 176) (SEQ ID NO: 22) BRAF_V600E_7 CUACAGAGAAAUCUCGAUG CUACAGAGAAAUCUCGAUG[dT][dT] (SEQ ID NO: 177) (SEQ ID NO: 23) BRAF_V600E_7_as CAUCGAGAUUUCUCUGUAG CAUCGAGAUUUCUCUGUAG[dT][dT] (SEQ ID NO: 178) (SEQ ID NO: 24) Table 7 – NRAS siRNAs siRNA Sense Sense sequence Antisense Antisenseincluding 3’ sequence including [dT][dT] 3’ [dT][dT] AUACUGGAUACA AUACUGGAUACAG UUCCAGCUGUAU UUCCAGCUGUAUC GCUGGAA (SEQ ID CUGGAA[dT][dT] CCAGUAU (SEQ ID CAGUAU[dT][dT] siRNA_1 NO: 25) (SEQ ID NO: 73) NO: 26) (SEQ ID NO: 74) UACUGGAUACAG UACUGGAUACAGC UUUCCAGCUGUA UUUCCAGCUGUAU CUGGAAA (SEQ ID UGGAAA[dT][dT] UCCAGUA (SEQ ID CCAGUA[dT][dT] siRNA_2 NO: 27) (SEQ ID NO: 75) NO: 28) (SEQ ID NO: 76) ACUGGAUACAGC ACUGGAUACAGCU UUUUCCAGCUGU UUUUCCAGCUGUA UGGAAAA (SEQ ID GGAAAA[dT][dT] AUCCAGU (SEQ ID UCCAGU[dT][dT] siRNA_3 NO: 29) (SEQ ID NO: 77) NO: 30) (SEQ ID NO: 78) CUGGAUACAGCU CUGGAUACAGCUG CUUUUCCAGCUG CUUUUCCAGCUGU GGAAAAG (SEQ ID GAAAAG[dT][dT] UAUCCAG (SEQ ID AUCCAG[dT][dT] siRNA_4 NO: 31) (SEQ ID NO: 79) NO: 32) (SEQ ID NO: 80) UGGAUACAGCUG UGGAUACAGCUGG UCUUUUCCAGCU UCUUUUCCAGCUG GAAAAGA (SEQ ID AAAAGA[dT][dT] GUAUCCA (SEQ ID UAUCCA[dT][dT] siRNA_5 NO: 33) (SEQ ID NO: 81) NO: 34) (SEQ ID NO: 82) GGAUACAGCUGG GGAUACAGCUGGA UUCUUUUCCAGC UUCUUUUCCAGCU AAAAGAA (SEQ ID AAAGAA[dT][dT] UGUAUCC (SEQ ID GUAUCC[dT][dT] siRNA_6 NO: 35) (SEQ ID NO: 83) NO: 36) (SEQ ID NO: 84) GAUACAGCUGGA GAUACAGCUGGAA CUUCUUUUCCAG CUUCUUUUCCAGC AAAGAAG (SEQ ID AAGAAG[dT][dT] CUGUAUC (SEQ ID UGUAUC[dT][dT] siRNA_7 NO: 37) (SEQ ID NO: 85) NO: 38) (SEQ ID NO: 86) AUACAGCUGGAA AUACAGCUGGAAA UCUUCUUUUCCA UCUUCUUUUCCAG AAGAAGA (SEQ ID AGAAGA[dT][dT] GCUGUAU(SEQ ID CUGUAU[dT][dT] siRNA_8 NO: 39) (SEQ ID NO: 71) NO: 40) (SEQ ID NO: 72) UACAGCUGGAAA UACAGCUGGAAAA CUCUUCUUUUCC CUCUUCUUUUCCA AGAAGAG (SEQ ID GAAGAG[dT][dT] AGCUGUA (SEQ ID GCUGUA[dT][dT] siRNA_9 NO: 41) (SEQ ID NO: 87) NO: 42) (SEQ ID NO: 88) ACAGCUGGAAAA ACAGCUGGAAAAG ACUCUUCUUUUC ACUCUUCUUUUCC GAAGAGU(SEQ ID AAGAGU[dT][dT] CAGCUGU (SEQ ID AGCUGU[dT][dT] siRNA_10 NO: 43) (SEQ ID NO: 89) NO: 44) (SEQ ID NO: 90) CAGCUGGAAAAG CAGCUGGAAAAGA UACUCUUCUUUU UACUCUUCUUUUC AAGAGUA (SEQ ID AGAGUA[dT][dT] CCAGCUG (SEQ ID CAGCUG[dT][dT] siRNA_11 NO: 45) (SEQ ID NO: 91) NO: 46) (SEQ ID NO: 92) AGCUGGAAAAGA AGCUGGAAAAGAA GUACUCUUCUUU GUACUCUUCUUUU AGAGUAC (SEQ ID GAGUAC[dT][dT] UCCAGCU (SEQ ID CCAGCU[dT][dT] siRNA_12 NO: 47) (SEQ ID NO: 93) NO: 48) (SEQ ID NO: 94) GCUGGAAAAGAA GCUGGAAAAGAAG UGUACUCUUCUU UGUACUCUUCUUU GAGUACA (SEQ ID AGUACA[dT][dT] UUCCAGC (SEQ ID UCCAGC[dT][dT] siRNA_13 NO: 49) (SEQ ID NO: 95) NO: 50) (SEQ ID NO: 96) CUGGAAAAGAAG CUGGAAAAGAAGA CUGUACUCUUCU CUGUACUCUUCUU AGUACAG (SEQ ID GUACAG[dT][dT] UUUCCAG (SEQ ID UUCCAG[dT][dT] siRNA_14 NO: 51) (SEQ ID NO: 97) NO: 52) (SEQ ID NO: 98) UGGAAAAGAAGA UGGAAAAGAAGAG ACUGUACUCUUC ACUGUACUCUUCU GUACAGU (SEQ ID UACAGU[dT][dT] UUUUCCA (SEQ ID UUUCCA[dT][dT] siRNA_15 NO: 53) (SEQ ID NO: 99) NO: 54) (SEQ ID NO: 100) GGAAAAGAAGAG GGAAAAGAAGAGU CACUGUACUCUU CACUGUACUCUUC UACAGUG (SEQ ID ACAGUG[dT][dT] CUUUUCC (SEQ ID UUUUCC[dT][dT] siRNA_16 NO: 55) (SEQ ID NO: 101) NO: 56) (SEQ ID NO: 102) GAAAAGAAGAGU GAAAAGAAGAGUA GCACUGUACUCU GCACUGUACUCUU ACAGUGC (SEQ ID CAGUGC[dT][dT] UCUUUUC (SEQ CUUUUC[dT][dT] siRNA_17 NO: 57) (SEQ ID NO: 103) ID NO: 58) (SEQ ID NO: 104) AAAAGAAGAGUA AAAAGAAGAGUAC GGCACUGUACUC GGCACUGUACUCU CAGUGCC (SEQ ID AGUGCC[dT][dT] UUCUUUU (SEQ UCUUUU[dT][dT] siRNA_18 NO: 59) (SEQ ID NO: 105) ID NO: 60) (SEQ ID NO: 106) AAAGAAGAGUAC AAAGAAGAGUACA UGGCACUGUACU UGGCACUGUACUC AGUGCCA (SEQ ID GUGCCA[dT][dT] CUUCUUU (SEQ UUCUUU[dT][dT] siRNA_19 NO: 61) (SEQ ID NO: 107) ID NO: 62) (SEQ ID NO: 108) Table 8 – RNA sequences (corresponding to the DNA sequences shown in Figure 14) siRNAAntisense SenseAUUUUGGUCUAGCUGCAGA (SEQ ID CCUGUAGCUAGACCAAAAU (SEQ ID siRNA_1 NO: 179) NO: 180) UUUUGGUCUAGCUACAGAG (SEQ ID CCCUGUAGCUAGACCAAAA (SEQ ID siRNA_2 NO:181) NO: 182) UUUGGUCUAGCUACAGAGA (SEQ ID UCCCUGUAGCUAGACCAAA (SEQ ID siRNA_3 NO:183) NO: 184) UUGGUCUAGCUACAGAGAA (SEQ ID UUCCCUGUAGCUAGACCAA (SEQ ID siRNA_4 NO: 185) NO: 186) UGGUCUAGCUACAGAGAAA (SEQ ID UUUCCCUGUAGCUAGACCA (SEQ ID siRNA_5 NO: 187) NO: 188) GGUCUAGCUACAGAGAAAU (SEQ ID AUUUCCCUGUAGCUAGACC (SEQ ID siRNA_6 NO: 189) NO: 190) GUCUAGCUACAGAGAAAUC (SEQ ID GAUUUCCCUGUAGCUAGAC (SEQ ID siRNA_7 NO: 165) NO: 203) UCUAGCUACAGAGAAAUCU (SEQ ID AGAUUUCCCUGUAGCUAGA (SEQ ID siRNA_8 NO: 167) NO: 204) CUAGCUACAGAGAAAUCUC (SEQ ID GAGAUUUCCCUGUAGCUAG (SEQ ID siRNA_9 NO: 169) NO: 205) UAGCUACAGAGAAAUCUCG (SEQ ID CGAGAUUUCCCUGUAGCUA (SEQ ID siRNA_10 NO: 171) NO: 206) AGCUACAGAGAAAUCUCGA (SEQ ID UCGAGAUUUCCCUGUAGCU (SEQ ID siRNA_11 NO: 173) NO: 207) GCUACAGAGAAAUCUCGAU (SEQ ID AUCGAGAUUUCCCUGUAGC (SEQ ID siRNA_12 NO: 175) NO: 208) CUACAGAGAAAUCUCGAUG (SEQ ID CAUCGAGAUUUCCCUGUAG (SEQ ID siRNA_13 NO: 177) NO: 209) UACAGAGAAAUCUCGAUGG (SEQ ID CCAUCGAGAUUUCCCUGUA (SEQ ID siRNA_14 NO: 191) NO: 192) ACAGAGAAAUCUCGAUGGA (SEQ ID UCCAUCGAGAUUUCCCUGU (SEQ ID siRNA_15 NO: 193) NO: 194) CAGAGAAAUCUCGAUGGAG (SEQ ID CUCCAUCGAGAUUUCCCUG (SEQ ID siRNA_16 NO: 195) NO: 196) AGAGAAAUCUCGAUGGAGU (SEQ ID ACUCCAUCGAGAUUUCCCU (SEQ ID siRNA_17 NO: 197) NO: 198) GAGAAAUCUCGAUGGAGUG (SEQ ID CACUCCAUCGAGAUUUCCC (SEQ ID siRNA_18 NO: 199) NO: 200) AGAAAUCUCGAUGGAGUGG (SEQ ID CCACUCCAUCGAGAUUUCC (SEQ ID siRNA_19 NO: 201) NO: 202) RNA quantification RNA expression levels were determined by RT-qPCR using the SYBR-Green assay of cDNA, synthesised by a reverse transcription reaction of RNA collected post-transfection. Primers were designed to differentially measure mutant and WT expression of each gene. RNA levels were normalised to the housekeeping gene GAPDH. The reaction was performed using Quantitative PCR QuantStudio 7 Flex. Measurement of cell proliferation and death Cancer cell lines were each seeded at 3,000 cells per well in a flat bottom 96-well plate (#3596, Corning) and left to grow overnight at 37°C, 5% CO2. The following day seeded cells were transfected with the most effective transfection agent according to previous transfection efficiency experiments in the High-Throughput Facility at The Francis Crick institute. Consequently, RNAiMAX (#13778075, ThermoFisher) at 0.1ul per well was selected. Cell lines were treated with siRNAs (previously selected for specificity using RT-qPCR) against oncogene variants both present and absent in each cancer cell line to control for non-specific effects of targeted siRNA treatment. siRNA complexes were allowed to form in reduced-serum Opti-MEM (#31985062, ThermoFisher) for 20 minutes. siRNAs were given as single 37.5nM treatments or in combination with one or two other siRNAs, at 18.75nM or 12.5nM each respectively. siRNAs combined to a total of 2 or 3 would each target an oncogene found to be in a single cell line. No media changes were performed after transfection until the end of the experiment. Confluency and Caspase 3 / 7 activity per well were measured over 5 to 6 days using the S3 Live-Cell Imaging Incucyte (Sartorius) in the High-Throughput Facility at The Francis Crick Institute. Plates were imaged at a 3-hour frequency, at an objective of 10X. Caspase 3 / 7 activity was measured using a DNA-binding fluorophore, NucView-488 (#10402, Biotium), that emits light at 530nm in the presence of activated caspases 3 and 7. Emitted light was measured using the green, fluorescent channel of the S3 Incucyte. The fluorophore was pipetted into each well to a final dilution of 1:200 (final concentration of 5uM, from a stock of 1mM in DMSO) on the day of transfection, just before the transfection. Plates were protected from light after addition of the fluorophore. Analysis of phase (confluency) and green imaging was completed by the basic analyser software of the S3 Incucyte, with the only parameter changed being phase set to -4. Data was exported and further analysis continued in Excel (Microsoft) and Prism version 10 (GraphPad). Mouse xenograft models Each NSG(IL2R-NSG) mouse received a single intratumoural injection of 50ul containing 250,000 cells in PBS:Matrigel (1:1). Delivery of siRNA to tumours with Avalanche®-in vivo Transfection Reagent according the manufacturer’s instructions. In brief, 50ul containing 2.8ul Avalanche, 12ug siRNA, 5% glucose. siRNA sequences Unless indicated otherwise, the siRNA sequences used in the Examples above are as follows (the same sequences without “[dT][dT]” are also provided in square brackets for reference). HCT-116 PIK3CA c.3140A>G p.H1047R Sequence 5’ -> 3’ Sense: UGAUGCACGUCAUGGUGGC [dT][dT] (SEQ ID NO:5) [UGAUGCACGUCAUGGUGGC (SEQ ID NO: 159)] Antisense: GCCACCAUGACGUGCAUCA [dT][dT] (SEQ ID NO:6) [GCCACCAUGACGUGCAUCA (SEQ ID NO: 160)] MW: 13,332 KRAS c.38G>A p.G13D Sequence 5’ -> 3’ Sense: GCUGGUGACGUAGGCAAGA [dT][dT] (SEQ ID NO: 63) [GCUGGUGACGUAGGCAAGA (SEQ ID NO: 210)] Antisense: UCUUGCCUACGUCACCAGC [dT][dT] (SEQ ID NO: 64) [UCUUGCCUACGUCACCAGC (SEQ ID NO: 211)] MW: 13,332 CTNNB1 c.133_135delTCT p.S45Del Sequence 5’ -> 3’ Sense: CCACAGUCCUCUGAGUGGU [dT][dT] (SEQ ID NOs: 65) [CCACAGUCCUCUGAGUGGU (SEQ ID NO: 212)] Antisense: ACCACUCAGAGGACUGUGG [dT][dT] (SEQ ID NOs: 66) [ACCACUCAGAGGACUGUGG (SEQ ID NO: 213)] siMaGiC, unless stated otherwise, in HCT-116: siMaGiC2: combination of siPIK3CA p.H1047R and siKRAS p.G13D siMaGiC3: combination of all of the above siRNAs (siPIK3CA, siKRAS and siCTNNB1) SK-OV-3 PIK3CA c.3140A>G p.H1047R Sequence 5’ -> 3’ Sense: UGAUGCACGUCAUGGUGGC [dT][dT] (SEQ ID NO:5) [UGAUGCACGUCAUGGUGGC (SEQ ID NO: 159)] Antisense: GCCACCAUGACGUGCAUCA [dT][dT] (SEQ ID NO:6) [GCCACCAUGACGUGCAUCA (SEQ ID NO: 160)] MW: 13332 FBXW7 c.1514G>T p.R505L Sequence 5’ -> 3’ Sense: CAGCAGUCCUCUGUGUUCA [dT][dT] (SEQ ID NO:7) [CAGCAGUCCUCUGUGUUCA (SEQ ID NO: 161)] Antisense: UGAACACAGAGGACUGCUG [dT][dT] (SEQ ID NO:8) [UGAACACAGAGGACUGCUG (SEQ ID NO: 162)] MW: 13317 APC c.4666del p.T1556fs Sequence 5’ -> 3’ Sense: UUGAUUCUGAAAGGACCU [dT][dT] (SEQ ID NO:9) [UUGAUUCUGAAAGGACCU (SEQ ID NO: 163)] Antisense: AGGUCCUUUCAGAAUCAA [dT][dT] (SEQ ID NO:10) [AGGUCCUUUCAGAAUCAA (SEQ ID NO: 164)] MW: 12637 siMaGiC, unless stated otherwise, in SK-OV-3: siMaGiC2: combination of siPIK3CA p.H1047R and siFBXW7 p.R505L siMaGiC3: combination of all of the above siRNAs (siPIK3CA, siFBXW7 and siAPC) MCF-7 PIK3CA c.1633G>A p.E545K Sequence 5’ -> 3’ Sense: GAAAUCACUAAGCAGGAGA [dT][dT] (SEQ ID NO:1) [GAAAUCACUAAGCAGGAGA (SEQ ID NO: 155)] Antisense: UCUCCUGCUUAGUGAUUUC [dT][dT] (SEQ ID NO:2) [UCUCCUGCUUAGUGAUUUC (SEQ ID NO: 156)] GATA3 c.1006dupG p.D336Gfs*17 Sequence 5’ -> 3’ Sense: UGCCAAUGGGGGACCCUGU [dT][dT] (SEQ ID NO: 67) [UGCCAAUGGGGGACCCUGU (SEQ ID NO: 214)] Antisense: ACAGGGUCCCCCAUUGGCA [dT][dT] (SEQ ID NO: 68) [ACAGGGUCCCCCAUUGGCA (SEQ ID NO: 215)] siMaGiC2 in MCF-7: combination of the above (siPIK3CA p.E545K and siGATA3) A2058 NRASc.181C>A p.Q61K5’ -> 3’ Sense: AUACAGCUGGAAAAGAAGA [dT][dT] (SEQ ID NO:71) [AUACAGCUGGAAAAGAAGA (SEQ ID NO: 39)] Antisense: UCUUCUUUUCCAGCUGUAU [dT][dT] (SEQ ID NO:72) [UCUUCUUUUCCAGCUGUAU (SEQ ID NO: 40)] MW: 13273 NRASc.182A>G p.Q61R5’ -> 3’ Sense: AGCUGGACGAGAAGAGUAC [dT][dT] (SEQ ID NO: 69) [AGCUGGACGAGAAGAGUAC (SEQ ID NO: 216)] Antisense: GUACUCUUCUCGUCCAGCU [dT][dT] (SEQ ID NO: 70) [GUACUCUUCUCGUCCAGCU (SEQ ID NO: 217)] MW: 13317 BRAF p.V600E Sequence 5’ -> 3’ Sense: CUAGCUACAGAGAAAUCUC [dT][dT] (SEQ ID NO:15) [CUAGCUACAGAGAAAUCUC (SEQ ID NO: 169)] Antisense: GAGAUUUCUCUGUAGCUAG [dT][dT] (SEQ ID NO:16) [GAGAUUUCUCUGUAGCUAG (SEQ ID NO: 170)] siCOMBO in A2058: all of the above 3 (siNRASc.181C>A p.Q61K, siNRASc.182A>G p.Q61Rand siBRAF) Commercially available siRNAs siCNTRL (Dharmacon ON-TARGETplus non-targeting control 1) siCNTRL (Qiagen, AllStars Negative Control)siUBB (Merck, NM_018955, SASI_Hs01_00201423)siARL6IP1 (L-004321-01-0005. ON-TARGETplus Human ARL6IP123204) siMYC (PDSIRNA2D - SASI_Hs01_00222676) The invention contemplates any combination of the siRNAs recited above. References 1. Li X. Dynamic changes of driver genes' mutations across clinical stages in nine cancer types. Cancer Med.2016;5(7):1556-65. 2. Abbosh C, Frankell AM, Harrison T, Kisistok J, Garnett A, Johnson L, et al. Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA. Nature.2023;616(7957):553-62. 3. Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. The New England journal of medicine.2012;366(10):883-92. 4. Jamal-Hanjani M, Hackshaw A, Ngai Y, Shaw J, Dive C, Quezada S, et al. Tracking genomic cancer evolution for precision medicine: the lung TRACERx study. PLoS Biol.2014;12(7):e1001906. 5. Downward J. Ras signalling and apoptosis. Curr Opin Genet Dev.1998;8(1):49-54. 6. Rajesh D, Schell K, Verma AK. Ras mutation, irrespective of cell type and p53 status, determines a cell's destiny to undergo apoptosis by okadaic acid, an inhibitor of protein phosphatase 1 and 2A. Mol Pharmacol.1999;56(3):515-25. 7. Leblanc V, Delumeau I, Tocque B. Ras-GTPase activating protein inhibition specifically induces apoptosis of tumour cells. Oncogene.1999;18(34):4884-9. 8. Harrington EA, Fanidi A, Evan GI. Oncogenes and cell death. Curr Opin Genet Dev. 1994;4(1):120-9. 9. Bryant D, Barberan-Martin, S., Maeshima, R., Del Valle Torres, I,. Rabii, M,. Baird, W., Sauvadet, A., Demetriou, C., Jones, P, Knöpfel, N., Michailidis, F., Riachi, M., Bennett, D.C,, Zecchin, D., Pittman, A., Polubothu, S., Hart, S., Kinsler, V.A. RNA therapy for oncogenic NRAS-driven naevi induces apoptosis.. Under review.2024. 10. Zill OA, Banks KC, Fairclough SR, Mortimer SA, Vowles JV, Mokhtari R, et al. The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients. Clinical cancer research : an official journal of the American Association for Cancer Research.2018;24(15):3528-38. 11. Kinsler VA, O'Hare P, Jacques T, Hargrave D, Slater O. MEK inhibition appears to improve symptom control in primary NRAS-driven CNS melanoma in children. British journal of cancer. 2017;116(8):990-3. 12. Martin SB, Polubothu S, Bruzos AL, Kelly G, Horswell S, Sauvadet A, et al. Mosaic BRAF Fusions Are a Recurrent Cause of Congenital Melanocytic Nevi Targetable by MAPK Pathway Inhibition. The Journal of investigative dermatology.2023. 13. Zecchin D, Knopfel N, Gluck AK, Stevenson M, Sauvadet A, Polubothu S, et al. GNAQ / GNA11 Mosaicism Causes Aberrant Calcium Signaling Susceptible to Targeted Therapeutics. The Journal of investigative dermatology.2023. 14. Bauer J, Bastian BC. Distinguishing melanocytic nevi from melanoma by DNA copy number changes: comparative genomic hybridization as a research and diagnostic tool. Dermatol Ther. 2006;19(1):40-9. 15. Kinsler VA, Polubothu S, Calonje JE, Chong WK, Thompson D, Jacques TS, et al. Copy number abnormalities in new or progressive 'neurocutaneous melanosis' confirm it to be primary CNS melanoma. Acta neuropathologica.2017;133(2):329-31. EMBODIMENTS The invention may also be understood by reference to the following numbered clauses. 1. A method of preparing a combinatorial treatment suitable for suppressing growth and / or inducing apoptosis in a tumour of a subject, the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; and b) providing a first nucleic acid molecule complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); thereby providing the combinatorial treatment. 2. A method of preparing a combinatorial treatment suitable for treating a tumour in a subject, the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; and b) providing a first nucleic acid molecule complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); thereby providing the combinatorial treatment. 3. A method of determining a treatment regimen suitable for suppressing growth and / or inducing apoptosis in a tumour in a subject; the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; and b) providing a first nucleic acid molecule complementary to an mRNA encoding a first pathogenic genomic sequence variant relevant to the tumour of the subject identified in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); thereby providing the treatment regimen. 4. A method of determining a treatment regimen for treating a tumour in a subject; the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; and b) providing a first nucleic acid molecule complementary to an mRNA encoding a first pathogenic genomic sequence variant relevant to the tumour of the subject identified in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); thereby providing the treatment regimen. 5. The method of any of clauses 1-4, further comprising providing one or more further nucleic acid molecules, wherein each further nucleic acid molecule is complementary to an mRNA of a further pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a). 6. The method of any of clauses 1-5, wherein the nucleic acid molecules are for simultaneous administration. 7. The method of any of clauses 1-6, wherein the nucleic acid molecules are for sequential administration in any order. 8. The method of any of clauses 1-7, wherein the nucleic acid molecules are formulated in a single composition. 9. A method of suppressing growth and / or inducing apoptosis in a tumour of a subject, the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; b) providing a first nucleic acid molecule complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); and c) administering the first and second nucleic acid molecules to the subject. 10. A method of treating a tumour in a subject, the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; b) providing a first nucleic acid molecule complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); and c) administering the first and second nucleic acid molecules to the subject. 11. The method of clause 9 or 10, further comprising providing one or more further nucleic acid molecules, wherein each further nucleic acid molecule is complementary to an mRNA of a further different pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a), and administering each further nucleic acid molecule to the subject. 12. The method of any of clauses 9-11, wherein the nucleic acid molecules are administered simultaneously. 13. The method of any of clauses 9-12, wherein the nucleic acid molecules are administered sequentially in any order. 14. The method of any of clauses 9-13, wherein the nucleic acid molecules are administered separately. 15. The method of any of clauses 9-14, wherein the nucleic acid molecules are formulated in a single composition. 16. The method of any of clauses 1-15, wherein the method further comprises a step of providing sequence information for the tumour of the subject, prior to step (a), and wherein step (a) comprises selecting the at least two different pathogenic genomic sequence variants based on the sequence information. 17. The method of clause 16, wherein the sequence information is obtained from genotyping a sample of the subject’s tumour. 18. The method of clause 17, wherein said genotyping comprises sequencing a sample of the subject’s tumour. 19. The method of clause 16, wherein providing sequence information for the tumour of the subject comprises sequencing a cell free RNA sample or a cell free DNA sample from the subject. 20. The method of clause 18 or 19, wherein the sequencing is ultra-deep sequencing. 21. The method of clause 18 or 19, wherein the sequencing is massively parallel sequencing-by- synthesis. 22. The method of clause 16, wherein the sequence information is obtained from a database. 23. The method of any of clauses 1-22, wherein step (a) comprises identifying at least one pathogenic genomic sequence variant relevant to the tumour of the subject based on known pathogenic genomic sequence variants for the same or similar tumour types. 24. The method of any of clauses 1-23, wherein step (a) comprises identifying at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten different pathogenic genomic sequence variants relevant to the tumour of the subject. 25. The method of any of clauses 1-24, wherein step (a) comprises identifying at least three different pathogenic genomic sequence variants relevant to the tumour of the subject. 26. The method of any of clauses 1-25, wherein step (a) comprises identifying at least four different pathogenic genomic sequence variants relevant to the tumour of the subject. 27. The method of any of clauses 1-26, wherein step (a) comprises identifying at least five different pathogenic genomic sequence variants relevant to the tumour of the subject. 28. The method of any of clauses 1-27, wherein the tumour is a benign tumour. 29. The method of any of clauses 1-27, wherein the tumour is a malignant tumour. 30. The method of any of clauses 1-27, wherein the tumour is a dysplastic lesion. 31. The method of any of clauses 1-28, wherein the tumour is a benign congenital tumour. 32. The method of any of clauses 1-27 or 29, wherein the tumour is a cancerous tumour. 33. The method of clause 32, wherein the cancer is selected from the group consisting of Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, Kaposi sarcoma, AIDS-related lymphoma, primary CNS lymphoma, anal cancer, appendix cancer, astrocytoma, brain cancer, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, breast cancer, Burkitt lymphoma, carcinoma, medulloblastoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocyte leukemia, chronic myelogenous leukemia, chronic myeloproliferative neoplasm, colorectal cancer, craniopharyngioma, ductal carcinoma, endometrial cancer, ependymoma, esophageal cancer, head and neck cancer, Ewing sarcoma, eye cancer, fallopian tube cancer, gallbladder cancer, gastric cancer, stomach cancer, leukemia, blood cancer, hepatocellular cancer, liver cancer, kidney cancer, lip cancer, lymphoma, laryngeal cancer, lung cancer, melanoma (optionally leptomeningeal melanocytic disease), merkel cell carcinoma, mesothelioma, mouth cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous neck cancer, stomach cancer, urethral cancer, uterine cancer, vaginal cancer, vascular cancer, vulvar cancer or a combination thereof. 34. The method of any of clauses 1-33, wherein the tumour is a lung, brain, bladder, endometrial, kidney, heart, ovarian, stomach, throat, mouth, head, neck, skin, pancreas, rectal, colon, penile, eye, connective tissue, fat, bone, prostate, thyroid, uterine, or liver tumour. 35. The method of any of clauses 1-34, wherein the tumour is a solid tumour. 36. The method of any of clauses 1-35, wherein the tumour is a congenital melanocytic naevus. 37. The method of any of clauses 1-34, wherein the tumour is an arteriovenous malformation (AVM). 38. The method of any of clauses 1-34, wherein the tumour is an acquired naevus. 39. The method of any preceding clause, wherein at least one of the pathogenic genomic sequence variants is a gain of function variant. 40. The method of any preceding clause, wherein at least one of the pathogenic genomic sequence variants is a loss of function variant. 41. The method of clause 40, wherein the tumour is heterozygous for the loss of function variant. 42. The method of any preceding clause, wherein at least one nucleic acid molecule preferentially hybridises to an mRNA of a pathogenic genomic sequence variant relative to an mRNA of a non-variant sequence of the same gene. 43. The method of any preceding clause, wherein at least two nucleic acid molecules preferentially hybridise to an mRNA of a pathogenic genomic sequence variant relative to an mRNA of a non-variant sequence of the same gene. 44. The method of any preceding clause, wherein all of the nucleic acid molecules preferentially hybridise to an mRNA of a pathogenic genomic sequence variant relative to an mRNA of a non-variant sequence of the same gene. 45. The method of any preceding clause, wherein at least one nucleic acid molecule preferentially inhibits the expression of a pathogenic genomic sequence variant relative to a non-variant sequence of the same gene. 46. The method of any preceding clause, wherein at least two nucleic acid molecules preferentially inhibit the expression of a pathogenic genomic sequence variant relative to a non-variant sequence of the same gene. 47. The method of any preceding clause, wherein all of the nucleic acid molecules preferentially inhibit the expression of a pathogenic genomic sequence variant relative to a non-variant sequence of the same gene. 48. The method of any preceding clause, wherein step (b) comprises providing at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten nucleic acid molecules. 49. The method of any preceding clause, wherein step (b) comprises providing at least three nucleic acid molecules. 50. The method of any preceding clause, wherein step (b) comprises providing at least four nucleic acid molecules. 51. The method of any preceding clause, wherein step (b) comprises providing at least five nucleic acid molecules. 52. The method of any preceding clause, wherein the first nucleic acid molecule is 10 to 50 nucleotides in length. 53. The method of any preceding clause, wherein the first nucleic acid molecule is 10 to 40 nucleotides in length. 54. The method of any preceding clause, wherein the first nucleic acid molecule is 10 to 30 nucleotides in length. 55. The method of any preceding clause, wherein the first nucleic acid molecule is 10 to 20 nucleotides in length. 56. The method of any preceding clause, wherein the first nucleic acid molecule is 15 to 30 nucleotides in length. 57. The method of any preceding clause, wherein the first nucleic acid molecule is 15 to 25 nucleotides in length. 58. The method of any preceding clause, wherein the first nucleic acid molecule is 20 to 30 nucleotides in length. 59. The method of any preceding clause, wherein the first nucleic acid molecule is 20 to 25 nucleotides in length. 60. The method of any preceding clause, wherein the second nucleic acid molecule is 10 to 50 nucleotides in length. 61. The method of any preceding clause, wherein the second nucleic acid molecule is 10 to 40 nucleotides in length. 62. The method of any preceding clause, wherein the second nucleic acid molecule is 10 to 30 nucleotides in length. 63. The method of any preceding clause, wherein the second nucleic acid molecule is 10 to 20 nucleotides in length. 64. The method of any preceding clause, wherein the second nucleic acid molecule is 15 to 30 nucleotides in length. 65. The method of any preceding clause, wherein the second nucleic acid molecule is 15 to 25 nucleotides in length. 66. The method of any preceding clause, wherein the second nucleic acid molecule is 20 to 30 nucleotides in length. 67. The method of any preceding clause, wherein the second nucleic acid molecule is 20 to 25 nucleotides in length. 68. The method of any preceding clause, wherein one or more further nucleic acid molecules, if present, are 10 to 50, 10 to 40, 10 to 30, 10 to 20, 15 to 30, 15 to 25, 20 to 30, 20 to 25, or 21 nucleotides in length. 69. The method of any preceding clause, wherein the first nucleic acid molecule is double stranded. 70. The method of any preceding clause wherein the first nucleic acid molecule comprises a first strand that is complementary to at least a portion of the mRNA of the first pathogenic genomic sequence variant, and further comprises a second strand complementary to the first strand. 71. The method of any preceding clause, wherein the first nucleic acid molecule is an siRNA. 72. The method of any preceding clause, wherein the second nucleic acid molecule is double stranded. 73. The method of any preceding clause, wherein the second nucleic acid molecule comprises a first strand that is complementary to at least a portion of the mRNA of the second pathogenic genomic sequence variant, and further comprises a second strand complementary to the first strand. 74. The method of any preceding clause, wherein the second nucleic acid molecule is an siRNA. 75. The method of any preceding clause, wherein one or more further nucleic acid molecules, if present, are double stranded. 76. The method of any preceding clause, wherein one or more further nucleic acid molecules, if present, are siRNAs. 77. The method of any preceding clause, wherein the first and second nucleic acid molecules are double stranded. 78. The method of any preceding clause, wherein the first and second nucleic acid molecules are siRNAs. 79. The method of any preceding clause, wherein at least one of the pathogenic genomic sequence variants is a variant of CDH1, MED12, ESR1, GATA3, KMT2C, MAP3K1, PTEN, LRP1B, ERBB4, NF1, ZFHX3, ERBB2, AKT1, ARID1A, ALK, PTPRT, RUNX1, BRCA2, EGFR, KRAS, TP53, LRP1B, PIK3CA, STK11, KEAP1, MET, RB1, KMT2D, ARID1A, KMT2C, FAT1, ALK, SMARCA4, CDKN2A, KRAS, BRAF, APC, FBXW7, SMAD4, RNF43, CTNNB1, FAT4, NRAS, TCF7L2, KMT2C, ATM, KMT2D, GNAS, AMER1, ATR, AR, ZFHX3, ATM, PTPRT, FHIT, GRIN2A, SPOP, RAD51B, CAMTA1, MYC, NOTCH2, GRIN2A, ROS1, KIT, PREX2, PTCH1, HRAS, KDR, DICER1, FOXL2, NTRK3 and / or CAMTA1. 80. The method of any preceding clause, wherein the nucleic acid molecules are administered intradermally. 81. The method of any preceding clause, wherein the nucleic acid molecules are administered intravenously. 82. The method of any preceding clause, wherein the nucleic acid molecules are administered orally. 83. The method of any preceding clause wherein one or more of the nucleic acid molecules are formulated for delivery as a lipid nanoparticle, a liposome, an exosome, a polymeric nanoparticle, an inorganic nanoparticle, a receptor-targeted nanoparticle, a receptor-targeted lipid nanoparticle or a ruxolitinib and thalidomide co-delivered polyelectrolyte nanocomplex (RTNP). 84. The method of any preceding clause, wherein one or more of the nucleic acid molecules are formulated for delivery as a lipid nanoparticle. 85. The method of any preceding clause, wherein one or more of the nucleic acid molecules are formulated for delivery as a receptor-targeted lipid nanoparticle. 86. The method of any preceding clause, wherein one or more of the nucleic acid molecules are encapsulated within a lipid nanoparticle or a receptor-targeted lipid nanoparticle. 87. The method of any preceding clause, wherein the nucleic acid molecules are administered by intradermal injection. 88. The method of any preceding clause, wherein the subject is a mammalian subject. 89. The method of any preceding clause, wherein the subject is a human subject. 90. A composition comprising at least two nucleic acid molecules, wherein the composition is suitable for inducing apoptosis in a tumour in a subject, wherein a first nucleic acid molecule comprises a sequence that is complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject, and each further nucleic acid molecule comprises a sequence that is complementary to an mRNA of a different pathogenic genomic sequence variant relevant to the tumour of the subject. 91. The composition of clause 90, with the proviso that the composition does not comprise both a nucleic acid molecule that is complementary to a variant NRAS mRNA, and a nucleic acid molecule that is complementary to a variant BRAF mRNA. 92. A combination comprising at least two nucleic acid molecules, wherein the combination is suitable for inducing apoptosis in a tumour in a subject; wherein a first nucleic acid molecule comprises a sequence that is complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject, and each further nucleic acid molecule comprises a sequence that is complementary to an mRNA of a different pathogenic genomic sequence variant relevant to the tumour of the subject. 93. The combination of clause 92, with the proviso that the combination does not comprise both a nucleic acid molecule that is complementary to a variant NRAS mRNA, and a nucleic acid molecule that is complementary to a variant BRAF mRNA. 94. The composition or combination of any of clauses 90-93, wherein the first and second nucleic acid molecules are for separate, sequential or simultaneous administration. 95. The composition or combination of any of clauses 90-94, wherein each different pathogenic genomic sequence variant is expressed by the tumour of the subject. 96. The composition or combination of any of clauses 90-95, comprising at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten nucleic acid molecules. 97. The composition or combination of any of clauses 90-96, comprising at least three nucleic acid molecules. 98. The composition or combination of any of clauses 90-97, comprising at least four nucleic acid molecules. 99. The composition or combination of any of clauses 90-98, comprising at least five nucleic acid molecules. 100. The composition or combination of any of clauses 90-99, wherein the nucleic acid molecules are formulated in a single composition. 101. The composition or combination of any of clauses 90-100, wherein the different pathogenic genomic sequence variants relevant to the tumour of the subject are identified by method further comprises a step of providing sequence information for the tumour of the subject, prior to step (a), and wherein step (a) comprises selecting the at least two different pathogenic genomic sequence variants based on the sequence information. 102. The composition or combination of any of clauses 90-101, wherein the different pathogenic genomic sequence variants relevant to the tumour of the subject are identified by genotyping a sample of the subject’s tumour. 103. The composition or combination of clause 102, wherein said genotyping comprises sequencing a sample of the subject’s tumour. 104. The composition or combination of any of clauses 90-103, wherein the different pathogenic genomic sequence variants relevant to the tumour of the subject are identified by sequencing a cell free RNA sample or a cell free DNA sample from the subject. 105. The composition or combination of any of clauses 103 or 104, wherein the sequencing is ultra-deep sequencing. 106. The composition or combination of any of clauses 103 or 104, wherein the sequencing is massively parallel sequencing-by-synthesis. 107. The composition or combination of any of clauses 90-106, wherein the different pathogenic genomic sequence variants relevant to the tumour of the subject are identified from a database. 108. The composition or combination of any of clauses 90-107, wherein the different pathogenic genomic sequence variants relevant to the tumour of the subject are identified based on known pathogenic genomic sequence variants for the same or similar tumour types. 109. The composition or combination of any of clauses 90-108, wherein the tumour is a benign tumour. 110. The composition or combination of any of clauses 90-108, wherein the tumour is a malignant tumour. 111. The composition or combination of any of clauses 90-108, wherein the tumour is a dysplastic lesion. 112. The composition or combination of any of clauses 90-109, wherein the tumour is a benign congenital tumour. 113. The composition or combination of any of clauses 90-108 or 110, wherein the tumour is a cancerous tumour. 114. The composition or combination of any clause 113, wherein the cancer is selected from the group consisting of Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, Kaposi sarcoma, AIDS-related lymphoma, primary CNS lymphoma, anal cancer, appendix cancer, astrocytoma, brain cancer, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, breast cancer, Burkitt lymphoma, carcinoma, medulloblastoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocyte leukemia, chronic myelogenous leukemia, chronic myeloproliferative neoplasm, colorectal cancer, craniopharyngioma, ductal carcinoma, endometrial cancer, ependymoma, esophageal cancer, head and neck cancer, Ewing sarcoma, eye cancer, fallopian tube cancer, gallbladder cancer, gastric cancer, stomach cancer, leukemia, blood cancer, hepatocellular cancer, liver cancer, kidney cancer, lip cancer, lymphoma, laryngeal cancer, lung cancer, melanoma, optionally leptomeningeal melanocytic disease, merkel cell carcinoma, mesothelioma, mouth cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous neck cancer, stomach cancer, urethral cancer, uterine cancer, vaginal cancer, vascular cancer, vulvar cancer or a combination thereof. 115. The composition or combination of any of clauses 90-114, wherein the tumour is a lung, brain, bladder, endometrial, kidney, heart, ovarian, stomach, throat, mouth, head, neck, skin, pancreas, rectal, colon, penile, eye, connective tissue, fat, bone, prostate, thyroid, uterine, or liver tumour. 116. The composition or combination of any of clauses 90-115, wherein the tumour is a solid tumour. 117. The composition or combination of any of clauses 90-116, wherein the tumour is a congenital melanocytic naevus. 118. The composition or combination of any of clauses 90-116, wherein the tumour is an arteriovenous malformation (AVM). 119. The composition or combination of any of clauses 90-116, wherein the tumour is an acquired naevus. 120. The composition or combination of any of clauses 90-119, wherein at least one of the pathogenic genomic sequence variants is a gain of function variant. 121. The composition or combination of any of clauses 90-120, wherein at least one of the pathogenic genomic sequence variants is a loss of function variant. 122. The composition or combination of clause 121, wherein the tumour is heterozygous for the loss of function variant. 123. The composition or combination of any of clauses 90-122, wherein at least one nucleic acid molecule preferentially hybridises to an mRNA of a pathogenic genomic sequence variant relative to an mRNA of a non-variant sequence of the same gene. 124. The composition or combination of any of clauses 90-123, wherein at least two nucleic acid molecules preferentially hybridise to an mRNA of a pathogenic genomic sequence variant relative to an mRNA of a non-variant sequence of the same gene. 125. The composition or combination of any of clauses 90-124, wherein all of the nucleic acid molecules preferentially hybridise to an mRNA of a pathogenic genomic sequence variant relative to an mRNA of a non-variant sequence of the same gene. 126. The composition or combination of any of clauses 90-125, wherein at least one nucleic acid molecule preferentially inhibits the expression of a pathogenic genomic sequence variant relative to a non-variant sequence of the same gene. 127. The composition or combination of any of clauses 90-126, wherein at least two nucleic acid molecules preferentially inhibit the expression of a pathogenic genomic sequence variant relative to a non-variant sequence of the same gene. 128. The composition or combination of any of clauses 90-127, wherein all of the nucleic acid molecules preferentially inhibit the expression of a pathogenic genomic sequence variant relative to a non-variant sequence of the same gene. 129. The composition or combination of any of clauses 90-128, wherein the first nucleic acid molecule is 10 to 50 nucleotides in length. 130. The composition or combination of any of clauses 90-129, wherein the first nucleic acid molecule is 10 to 40 nucleotides in length. 131. The composition or combination of any of clauses 90-130, wherein the first nucleic acid molecule is 10 to 30 nucleotides in length. 132. The composition or combination of any of clauses 90-131, wherein the first nucleic acid molecule is 10 to 20 nucleotides in length. 133. The composition or combination of any of clauses 90-132, wherein the first nucleic acid molecule is 15 to 30 nucleotides in length. 134. The composition or combination of any of clauses 90-133, wherein the first nucleic acid molecule is 15 to 25 nucleotides in length. 135. The composition or combination of any of clauses 90-134, wherein the first nucleic acid molecule is 20 to 30 nucleotides in length. 136. The composition or combination of any of clauses 90-135, wherein the first nucleic acid molecule is 20 to 25 nucleotides in length. 137. The composition or combination of any of clauses 90-136, wherein the second nucleic acid molecule is 10 to 50 nucleotides in length. 138. The composition or combination of any of clauses 90-137, wherein the second nucleic acid molecule is 10 to 40 nucleotides in length. 139. The composition or combination of any of clauses 90-138, wherein the second nucleic acid molecule is 10 to 30 nucleotides in length. 140. The composition or combination of any of clauses 90-139, wherein the second nucleic acid molecule is 10 to 20 nucleotides in length. 141. The composition or combination of any of clauses 90-140, wherein the second nucleic acid molecule is 15 to 30 nucleotides in length. 142. The composition or combination of any of clauses 90-141, wherein the second nucleic acid molecule is 15 to 25 nucleotides in length. 143. The composition or combination of any of clauses 90-142, wherein the second nucleic acid molecule is 20 to 30 nucleotides in length. 144. The composition or combination of any of clauses 90-143, wherein the second nucleic acid molecule is 20 to 25 nucleotides in length. 145. The composition or combination of any of clauses 90-144, wherein one or more further nucleic acid molecules, if present, are 10 to 50, 10 to 40, 10 to 30, 10 to 20, 15 to 30, 15 to 25, 20 to 30, 20 to 25, or 21 nucleotides in length. 146. The composition or combination of any of clauses 90-145, wherein the first nucleic acid molecule is double stranded. 147. The composition or combination of any of clauses 90-146, wherein the first nucleic acid molecule comprises a first strand that is complementary to at least a portion of the mRNA of the first pathogenic genomic sequence variant, and further comprises a second strand complementary to the first strand. 148. The composition or combination of any of clauses 90-147, wherein the first nucleic acid molecule is an siRNA. 149. The composition or combination of any of clauses 90-148, wherein the second nucleic acid molecule is double stranded. 150. The composition or combination of any of clauses 90-149, wherein the second nucleic acid molecule comprises a first strand that is complementary to at least a portion of the mRNA of the second pathogenic genomic sequence variant, and further comprises a second strand complementary to the first strand. 151. The composition or combination of any of clauses 90-150, wherein the second nucleic acid molecule is an siRNA. 152. The composition or combination of any of clauses 90-151, wherein one or more further nucleic acid molecules, if present, are double stranded. 153. The composition or combination of any of clauses 90-152, wherein one or more further nucleic acid molecules, if present, are siRNAs. 154. The composition or combination of any of clauses 90-153, wherein the first and second nucleic acid molecules are double stranded. 155. The composition or combination of any of clauses 90-154, wherein the first and second nucleic acid molecules are siRNAs. 156. The composition or combination of any of clauses 90-155, wherein at least one of the pathogenic genomic sequence variants is a variant of CDH1, MED12, ESR1, GATA3, KMT2C, MAP3K1, PTEN, LRP1B, ERBB4, NF1, ZFHX3, ERBB2, AKT1, ARID1A, ALK, PTPRT, RUNX1, BRCA2, EGFR, KRAS, TP53, LRP1B, PIK3CA, STK11, KEAP1, MET, RB1, KMT2D, ARID1A, KMT2C, FAT1, ALK, SMARCA4, CDKN2A, KRAS, BRAF, APC, FBXW7, SMAD4, RNF43, CTNNB1, FAT4, NRAS, TCF7L2, KMT2C, ATM, KMT2D, GNAS, AMER1, ATR, AR, ZFHX3, ATM, PTPRT, FHIT, GRIN2A, SPOP, RAD51B, CAMTA1, MYC, NOTCH2, GRIN2A, ROS1, KIT, PREX2, PTCH1, HRAS, KDR, DICER1, FOXL2, NTRK3 and / or CAMTA1. 157. The composition or combination of any of clauses 90-156, wherein one or more of the nucleic acid molecules are formulated for intradermal administration. 158. The composition or combination of any of clauses 90-157 wherein one or more of the nucleic acid molecules are formulated for intravenous administration. 159. The composition or combination of any of clauses 90-158, wherein one or more of the nucleic acid molecules are formulated for oral administration. 160. The composition or combination of any of clauses 90-159, wherein one or more of the nucleic acid molecules are formulated for delivery as a lipid nanoparticle, a liposome, an exosome, a polymeric nanoparticle, an inorganic nanoparticle, a receptor-targeted nanoparticle, a receptor-targeted lipid nanoparticle or a ruxolitinib and thalidomide co- delivered polyelectrolyte nanocomplex (RTNP). 161. The composition or combination of any of clauses 90-160, wherein one or more of the nucleic acid molecules are formulated for delivery as a lipid nanoparticle. 162. The composition or combination of any of clauses 90-161, wherein one or more of the nucleic acid molecules are formulated for delivery as a receptor-targeted lipid nanoparticle. 163. The composition or combination of any of clauses 90-162, wherein one or more of the nucleic acid molecules are encapsulated within a lipid nanoparticle or a receptor-targeted lipid nanoparticle. 164. The composition or combination of any of clauses 90-163, wherein the subject is a mammalian subject. 165. The composition or combination of any of clauses 90-164, wherein the subject is a human subject. 166. The composition or combination of any of clauses 90-165, for use in a method of inducing apoptosis in a tumour of a subject. 167. The composition or combination of any of clauses 90-165, for use in a method of suppressing growth of a tumour of a subject. 168. The composition or combination of any of clauses 90-165, for use in a method of treating cancer in a subject. 169. The composition or combination for use of any of clauses 166-168, wherein the method comprises: a) identifying at least two pathogenic genomic sequence variants relevant to the tumour of the subject; wherein the first nucleic acid molecule comprises a sequence that is complementary to an mRNA of a pathogenic genomic sequence variant identified in step (a), and wherein each further nucleic acid comprise a sequence that is complementary to an mRNA of a different pathogenic genomic sequence variant identified in step (a). 170. The composition or combination for use of any of clauses 166-169, the method comprising administering the composition or combination to the subject. 171. The composition or combination for use of clause 169 or 170, wherein step (a) comprises genotyping the subject’s tumour or a sample of the subject’s tumour. 172. The composition or combination for use of clause 171, wherein said genotyping comprises sequencing the subject’s tumour or a sample of the subject’s tumour. 173. The composition or combination for use of any of clauses 169-172, wherein step (a) comprises sequencing a cell free RNA sample or a cell free DNA sample from the subject. 174. The composition or combination for use of clause 172 or 173, wherein the sequencing is ultra-deep sequencing. 175. The composition or combination for use of clause 172 or 173, wherein the sequencing is massively parallel sequencing-by-synthesis. 176. The composition or combination for use of any of clauses 169-175, wherein step (a) comprises predicting at least one pathogenic genomic sequence variant expressed in the tumour of the subject based on known pathogenic genomic sequence variants for the same or similar tumour types. 177. The method, composition or combination of any preceding clause, wherein the first nucleic acid molecule comprises one or more chemical modifications. 178. The method, composition or combination of any preceding clause, wherein the second nucleic acid molecule comprises one or more chemical modifications. 179. The method, composition or combination of any preceding clause, wherein any further nucleic acid molecule comprises one or more chemical modifications. 180. The method, composition or combination of any of clauses 177-179, wherein the chemical modification is selected from the group consisting of a chemically modified nucleobase, a chemically modified sugar moiety and a chemically modified internucleoside linkage. 181. The composition or combination of any of clauses 90-165, or for use of any of clauses 166-176, with the proviso that the composition or combination does not comprise both a nucleic acid molecule that is complementary to a variant GNAQ mRNA, and a nucleic acid molecule that is complementary to a variant GNA11 mRNA. 182. The method, composition, combination, composition for use or combination for use according to any proceedings clause, wherein the pathogenic genomic sequence variants are oncogenic genomic sequence variants. 183. The method, composition, combination, composition for use or combination for use according to any proceedings clause, wherein the oncogenic genomic sequence variants are not variants of TP53. 184. The method, composition, combination, composition for use or combination for use according to any proceedings clause, wherein the oncogenic genomic sequence variants are not variants of KRAS. 185. The method, composition, combination, composition for use or combination for use according to any proceedings clause, wherein the oncogenic genomic sequence variants are not variants of ERCC1. 186. The method, composition, combination, composition for use or combination for use according to any proceedings clause, wherein the oncogenic genomic sequence variants are not variants of BRCA1. 187. The method, composition, combination, composition for use or combination for use according to any proceedings clause, wherein the oncogenic genomic sequence variants are not variants of MET. 188. The method, composition, combination, composition for use or combination for use according to any proceedings clause, wherein the oncogenic genomic sequence variants are not variants of EGFR. 189. The method, composition, combination, composition for use or combination for use according to any proceedings clause, wherein the oncogenic genomic sequence variants are not variants of PIK3CD. 190. The method, composition, combination, composition for use or combination for use according to any proceedings clause, wherein the oncogenic genomic sequence variants are not variants of FGFR3. 191. The method, composition, combination, composition for use or combination for use according to any proceedings clause, wherein the oncogenic genomic sequence variants are not variants of TSC2. 192. The method, composition, combination, composition for use or combination for use according to any proceedings clause, wherein the oncogenic genomic sequence variants are not variants of RASGRP2. 193. The method, composition, combination, composition for use or combination for use according to any proceedings clause, wherein the oncogenic genomic sequence variants are not variants of ITGA4. 194. The method, composition, combination, composition for use or combination for use according to any proceedings clause, wherein the oncogenic genomic sequence variants are not variants of NF1. 195. The method, composition, combination, composition for use or combination for use according to any proceedings clause, wherein the oncogenic genomic sequence variants are not variants of BAK1. 196. The method, composition, combination, composition for use or combination for use according to any proceedings clause, wherein the pathogenic genomic sequence variants are not variants of TP53, NRAS or BRAF. 197. The method, composition, combination, composition for use or combination for use according to any proceeding clause, wherein the first nucleic acid molecule is complementary to an mRNA of variant NRAS and the second nucleic acid molecule is complementary to an mRNA of variant MYC. 198. The method, composition, combination, composition for use or combination for use of any of clauses 1-196, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CA2 (PIK3CAc.1633G>A p.E545K) and the second nucleic acid molecule is complementary to an mRNA of variant GATA3. 199. The method, composition, combination, composition for use or combination for use of any of clauses 1-196, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CA1 (PIK3CAc.3140A>G p.H1047R) and the second nucleic acid molecule is complementary to an mRNA of variant FBXW7. 200. The method, composition, combination, composition for use or combination for use of any of clauses 1-196, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CAc.3140A>G p.H1047Rand the second nucleic acid molecule is complementary to an mRNA of variant CTNNB1c.133_135delTCT p.S45Del. 201. The method, composition, combination, composition for use or combination for use of any of clauses 1-196, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CAc.3140A>G p.H1047Rand the second nucleic acid molecule is complementary to an mRNA of variant KRASc.38G>A p.G13D. 202. The method, composition, combination, composition for use or combination for use of any of clauses 1-196, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CAc.3140A>G p.H1047Rand the second nucleic acid molecule is complementary to an mRNA of variant FBXW7c.1514G>T p.R505L. 203. The method, composition, combination, composition for use or combination for use of any of clauses 1-196, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CAc.1633G>A p.E545Kand the second nucleic acid molecule is complementary to an mRNA of variant GATA3c.1006dupG p.D336Gfs*17. 204. The method, composition, combination, composition for use or combination for use of any of clauses 1-196, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CA1 (PIK3CAc.3140A>G p.H1047R), the second nucleic acid molecule is complementary to an mRNA of variant FBXW7 and the further nucleic acid molecule is complementary to an mRNA of variant APC. The method, composition, combination, composition for use or combination for use of any of clauses 1-196, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CAc.3140A>G p.H1047R, the second nucleic acid molecule is complementary to an mRNA of variant KRASc.38G>A p.G13Dand the further nucleic acid molecule is complementary to an mRNA of variant CTNNB1c.133_135delTCT p.S45Del. The method, composition, combination, composition for use or combination for use of any of clauses 1-196, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CAc.3140A>G p.H1047R, the second nucleic acid molecule is complementary to an mRNA of variant FBXW7c.1514G>T p.R505Land the further nucleic acid molecule is complementary to an mRNA of variant APCc.4666del p.T1556fs. The method, composition, combination, composition for use or combination for use of any of clauses 1-196, wherein the first nucleic acid molecule is complementary to an mRNA of variant NRASp.Q61K, optionally NRASc.181C>A p.Q61K) the second nucleic acid molecule is complementary to an mRNA of variant NRASp.Q61R, optionally NRASc.182A>G p.Q61R) and the further nucleic acid molecule is complementary to an mRNA of variant BRAFp.V600E.

[0002] 208. The composition of clause 91, with the further proviso that the composition does not comprise a nucleic acid molecule that is complementary to a variant TP53 mRNA. 209. The method, composition, combination, composition for use or combination for use of any preceding clauses, wherein the first nucleic acid molecule is complementary to an mRNA of variant NRAS, and the second nucleic acid molecule is complementary to an mRNA of variant MYC. 210. The method, composition, combination, composition for use or combination for use of any one of clauses 1-208, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CA1 (PIK3CAc.3140A>G p.H1047R), and the second nucleic acid molecule is complementary to an mRNA of variant FBXW7. 211. The method, composition, combination, composition for use or combination for use of any one of clauses 1-208, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CA1 (PIK3CAc.3140A>G p.H1047R), the second nucleic acid molecule is complementary to an mRNA of variant FBXW7, and the third nucleic acid molecule is complementary to an mRNA of variant APC. 212. The method, composition, combination, composition for use or combination for use of any one of clauses 1-208, wherein the first nucleic acid molecule is complementary to an mRNA of PIK3CAc.3140A>G p.H1047R, and the second nucleic acid molecule is complementary to an mRNA of CTNNB1c.133_135delTCT p.S45Del. 213. The method, composition, combination, composition for use or combination for use of any one of clauses 1-208, wherein the first nucleic acid molecule is complementary to an mRNA of PIK3CAc.3140A>G p.H1047R, and the second nucleic acid molecule is complementary to an mRNA of KRASc.38G>A p.G13D. 214. The method, composition, combination, composition for use or combination for use of any one of clauses 1-208, wherein the first nucleic acid molecule is complementary to an mRNA of PIK3CAc.3140A>G p.H1047R, the second nucleic acid molecule is complementary to an mRNA of KRASc.38G>A p.G13D, and the third nucleic acid molecule is complementary to an mRNA of CTNNB1c.133_135delTCT p.S45Del. 215. The method, composition, combination, composition for use or combination for use of any one of clauses 1-208, wherein the first nucleic acid molecule is complementary to an mRNA of PIK3CAc.3140A>G p.H1047R, and the second nucleic acid molecule is complementary to an mRNA of FBXW7c.1514G>T p.R505L. 216. The method, composition, combination, composition for use or combination for use of any one of clauses 1-208, wherein the first nucleic acid molecule is complementary to an mRNA of PIK3CAc.3140A>G p.H1047R, the second nucleic acid molecule is complementary to an mRNA of FBXW7c.1514G>T p.R505L, and the third nucleic acid molecule is complementary to an mRNA of APCc.4666del p.T1556fs. 217. The method, composition, combination, composition for use or combination for use of any one of clauses 1-208, wherein the first nucleic acid molecule is complementary to an mRNA of PIK3CAc.1633G>A p.E545K, and the second nucleic acid molecule is complementary to an mRNA of GATA3c.1006dupG p.D336Gfs*17. 218. The method, composition, combination, composition for use or combination for use of any one of clauses 1-208, wherein the first nucleic acid molecule is complementary to an mRNA of NRASp.Q61K(for example, NRASc.181C>A p.Q61K), the second nucleic acid molecule is complementary to an mRNA of NRASp.Q61R(for example, NRASc.182A>G p.Q61R), and the third nucleic acid molecule is complementary to an mRNA of BRAFp.V600E. EQUIVALENTS AND SCOPE Those skilled in the art will appreciate that the present invention is defined by the appended claims and not by the Examples or other description of certain embodiments included herein. Similarly, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Unless defined otherwise above, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention. Generally, nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, genetics and protein and nucleic acid chemistry described herein are those well-known and commonly used in the art, or according to manufacturer’s specifications. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

Claims

CLAIMS 1. A method of preparing a combinatorial treatment suitable for suppressing growth and / or inducing apoptosis in a tumour of a subject, the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; and b) providing a first nucleic acid molecule complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); thereby providing the combinatorial treatment.

2. A method of preparing a combinatorial treatment suitable for treating a tumour in a subject, the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; and b) providing a first nucleic acid molecule complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); thereby providing the combinatorial treatment.

3. A method of determining a treatment regimen suitable for suppressing growth and / or inducing apoptosis in a tumour in a subject; the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; and b) providing a first nucleic acid molecule complementary to an mRNA encoding a first pathogenic genomic sequence variant relevant to the tumour of the subject identified in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); thereby providing the treatment regimen.

4. A method of determining a treatment regimen for treating a tumour in a subject; the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; andb) providing a first nucleic acid molecule complementary to an mRNA encoding a first pathogenic genomic sequence variant relevant to the tumour of the subject identified in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); thereby providing the treatment regimen.

5. The method of any of claims 1-4, further comprising providing one or more further nucleic acid molecules, wherein each further nucleic acid molecule is complementary to an mRNA of a further pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a).

6. A method of suppressing growth and / or inducing apoptosis in a tumour of a subject, the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; b) providing a first nucleic acid molecule complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); and c) administering the first and second nucleic acid molecules to the subject.

7. A method of treating a tumour in a subject, the method comprising: a) selecting at least two different pathogenic genomic sequence variants relevant to the tumour of the subject; b) providing a first nucleic acid molecule complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a), and providing a second nucleic acid molecule complementary to an mRNA of a second pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a); and c) administering the first and second nucleic acid molecules to the subject.

8. The method of claim 6 or 7, further comprising providing one or more further nucleic acid molecules, wherein each further nucleic acid molecule is complementary to an mRNA of a further different pathogenic genomic sequence variant relevant to the tumour of the subject selected in step (a), and administering each further nucleic acid molecule to the subject.

9. The method of any preceding claim, wherein step (a) comprises identifying at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten different pathogenic genomic sequence variants relevant to the tumour of the subject.

10. The method of any of claims 1-9, wherein the tumour is a benign tumour.

11. The method of any of claims 1-9, wherein the tumour is a cancerous tumour.

12. The method of claim 11, wherein the cancer is selected from the group consisting of Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, Kaposi sarcoma, AIDS-related lymphoma, primary CNS lymphoma, anal cancer, appendix cancer, astrocytoma, brain cancer, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, breast cancer, Burkitt lymphoma, carcinoma, medulloblastoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocyte leukemia, chronic myelogenous leukemia, chronic myeloproliferative neoplasm, colorectal cancer, craniopharyngioma, ductal carcinoma, endometrial cancer, ependymoma, esophageal cancer, head and neck cancer, Ewing sarcoma, eye cancer, fallopian tube cancer, gallbladder cancer, gastric cancer, stomach cancer, leukemia, blood cancer, hepatocellular cancer, liver cancer, kidney cancer, lip cancer, lymphoma, laryngeal cancer, lung cancer, melanoma, optionally leptomeningeal melanocytic disease, merkel cell carcinoma, mesothelioma, mouth cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous neck cancer, stomach cancer, urethral cancer, uterine cancer, vaginal cancer, vascular cancer, vulvar cancer or a combination thereof.

13. The method of any preceding claim, wherein at least one of the pathogenic genomic sequence variants is a gain of function variant.

14. The method of any preceding claim, wherein at least one of the pathogenic genomic sequence variants is a loss of function variant.

15. The method of any preceding claim, wherein at least one nucleic acid molecule preferentially hybridises to an mRNA of a pathogenic genomic sequence variant relative to an mRNA of a non-variant sequence of the same gene.

16. The method of any preceding claim, wherein the first nucleic acid molecule is 10 to 50 nucleotides in length.

17. The method of any preceding claim, wherein the second nucleic acid molecule is 10 to 50 nucleotides in length.

18. The method of any preceding claim, wherein the first nucleic acid molecule is an siRNA.

19. The method of any preceding claim, wherein the second nucleic acid molecule is an siRNA.

20. The method of any preceding claim, wherein at least one of the pathogenic genomic sequence variants is a variant of CDH1, MED12, ESR1, GATA3, KMT2C, MAP3K1, PTEN, LRP1B, ERBB4, NF1, ZFHX3, ERBB2, AKT1, ARID1A, ALK, PTPRT, RUNX1, BRCA2, EGFR, KRAS, TP53, LRP1B, PIK3CA, STK11, KEAP1, MET, RB1, KMT2D, ARID1A, KMT2C, FAT1, ALK, SMARCA4, CDKN2A, KRAS, BRAF, APC, FBXW7, SMAD4, RNF43, CTNNB1, FAT4, NRAS, TCF7L2, KMT2C, ATM, KMT2D, GNAS, AMER1, ATR, AR, ZFHX3, ATM, PTPRT, FHIT, GRIN2A, SPOP, RAD51B, CAMTA1, MYC, NOTCH2, GRIN2A, ROS1, KIT, PREX2, PTCH1, HRAS, KDR, DICER1, FOXL2, NTRK3 and / or CAMTA1.

21. The method of any preceding claim, wherein the nucleic acid molecules are administered intradermally, intravenously, or orally.

22. The method of any preceding claim wherein one or more of the nucleic acid molecules are formulated for delivery as a lipid nanoparticle, a liposome, an exosome, a polymeric nanoparticle, an inorganic nanoparticle, a receptor-targeted nanoparticle, a receptor-targeted lipid nanoparticle or a ruxolitinib and thalidomide co-delivered polyelectrolyte nanocomplex (RTNP).

23. The method of any preceding claim, wherein the subject is a mammalian subject, preferably a human subject.

24. A composition comprising at least two nucleic acid molecules, wherein the composition is suitable for inducing apoptosis in a tumour in a subject, wherein a first nucleic acid molecule comprises a sequence that is complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject, and each further nucleic acid molecule comprises a sequence that is complementary to an mRNA of a different pathogenic genomic sequence variant relevant to the tumour of the subject.

25. A combination comprising at least two nucleic acid molecules, wherein the combination is suitable for inducing apoptosis in a tumour in a subject; wherein a first nucleic acid molecule comprises a sequence that is complementary to an mRNA of a first pathogenic genomic sequence variant relevant to the tumour of the subject, and each further nucleic acid molecule comprises a sequence that is complementary to an mRNA of a different pathogenic genomic sequence variant relevant to the tumour of the subject.

26. The composition of claim 24 or combination of claim 25, with the proviso that the composition or combination does not comprise both a nucleic acid molecule that is complementary to a variant NRAS mRNA, and a nucleic acid molecule that is complementary to a variant BRAF mRNA.

27. The composition or combination of any of claims 24-26, wherein at least one of the pathogenic genomic sequence variants is a gain of function variant.

28. The composition or combination of any of claims 24-27, wherein at least one of the pathogenic genomic sequence variants is a loss of function variant.

29. The composition or combination of any of claims 24-28, wherein at least one nucleic acid molecule preferentially hybridises to an mRNA of a pathogenic genomic sequence variant relative to an mRNA of a non-variant sequence of the same gene.

30. The composition or combination of any of claims 24-29, wherein the first nucleic acid molecule is an siRNA.

31. The composition or combination of any of claims 24-30, wherein the second nucleic acid molecule is an siRNA.

32. The composition or combination of any of claims 24-31, wherein at least one of the pathogenic genomic sequence variants is a variant of CDH1, MED12, ESR1, GATA3, KMT2C, MAP3K1, PTEN, LRP1B, ERBB4, NF1, ZFHX3, ERBB2, AKT1, ARID1A, ALK, PTPRT, RUNX1, BRCA2, EGFR, KRAS, TP53, LRP1B, PIK3CA, STK11, KEAP1, MET, RB1, KMT2D, ARID1A, KMT2C, FAT1, ALK, SMARCA4, CDKN2A, KRAS, BRAF, APC, FBXW7, SMAD4, RNF43, CTNNB1, FAT4, NRAS, TCF7L2, KMT2C, ATM, KMT2D, GNAS, AMER1, ATR, AR, ZFHX3, ATM, PTPRT, FHIT, GRIN2A, SPOP, RAD51B, CAMTA1, MYC, NOTCH2, GRIN2A, ROS1, KIT, PREX2, PTCH1, HRAS, KDR, DICER1, FOXL2, NTRK3 and / or CAMTA1.

33. The composition or combination of any of claims 24-32, wherein one or more of the nucleic acid molecules are formulated for intradermal, intravenous, or oral administration.

34. The composition or combination of any of claims 24-33, wherein one or more of the nucleic acid molecules are formulated for delivery as a lipid nanoparticle, a liposome, an exosome, a polymeric nanoparticle, an inorganic nanoparticle, a receptor-targeted nanoparticle, a receptor-targeted lipid nanoparticle or a ruxolitinib and thalidomide co-delivered polyelectrolyte nanocomplex (RTNP).

35. The composition or combination of any of claims 24-34, for use in a method of inducing apoptosis in a tumour of a subject.

36. The composition or combination of any of claims 24-34, for use in a method of suppressing growth of a tumour of a subject.

37. The composition or combination of any of claims 24-34, for use in a method of treating cancer in a subject.

38. The method, composition, combination, composition for use or combination for use according to any proceeding claim, wherein the pathogenic genomic sequence variants are oncogenic genomic sequence variants.

39. The method, composition, combination, composition for use or combination for use according to any proceeding claim, wherein the first nucleic acid molecule is complementary to an mRNA of variant NRAS and the second nucleic acid molecule is complementary to an mRNA of variant MYC.

40. The method, composition, combination, composition for use or combination for use of any of claims 1-39, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CA2 (PIK3CAc.1633G>A p.E545K) and the second nucleic acid molecule is complementary to an mRNA of variant GATA3.

41. The method, composition, combination, composition for use or combination for use of any of claims 1-39, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CA1 (PIK3CAc.3140A>G p.H1047R) and the second nucleic acid molecule is complementary to an mRNA of variant FBXW7.

42. The method, composition, combination, composition for use or combination for use of any of claims 1-39, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CAc.3140A>G p.H1047Rand the second nucleic acid molecule is complementary to an mRNA of variant CTNNB1c.133_135delTCT p.S45Del.

43. The method, composition, combination, composition for use or combination for use of any of claims 1-39, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CAc.3140A>G p.H1047Rand the second nucleic acid molecule is complementary to an mRNA of variant KRASc.38G>A p.G13D.

44. The method, composition, combination, composition for use or combination for use of any of claims 1-39, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CAc.3140A>G p.H1047Rand the second nucleic acid molecule is complementary to an mRNA of variant FBXW7c.1514G>T p.R505L.

45. The method, composition, combination, composition for use or combination for use of any of claims 1-39, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CAc.1633G>A p.E545Kand the second nucleic acid molecule is complementary to an mRNA of variant GATA3c.1006dupG p.D336Gfs*17.

46. The method, composition, combination, composition for use or combination for use of any of claims 1-39, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CA1 (PIK3CAc.3140A>G p.H1047R), the second nucleic acid molecule is complementary to an mRNA of variant FBXW7 and the further nucleic acid molecule is complementary to an mRNA of variant APC.

47. The method, composition, combination, composition for use or combination for use of any of claims 1-39, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CAc.3140A>G p.H1047R, the second nucleic acid molecule is complementary to an mRNA of variant KRASc.38G>A p.G13Dand the further nucleic acid molecule is complementary to an mRNA of variant CTNNB1c.133_135delTCT p.S45Del.

48. The method, composition, combination, composition for use or combination for use of any of claims 1-39, wherein the first nucleic acid molecule is complementary to an mRNA of variant PIK3CAc.3140A>G p.H1047R, the second nucleic acid molecule is complementary to an mRNA of variant FBXW7c.1514G>T p.R505Land the further nucleic acid molecule is complementary to an mRNA of variant APCc.4666del p.T1556fs.

49. The method, composition, combination, composition for use or combination for use of any of claims 1-39, wherein the first nucleic acid molecule is complementary to an mRNA of variant NRASp. Q61K, optionally NRASc.181C>A p.Q61K, the second nucleic acid molecule is complementary to an mRNA of variant NRASp.Q61R (optinoally NRASc.182A>G p.Q61R) and the further nucleic acidmolecule is complementary to an mRNA of variant BRAFp.V600E.

50. The composition of claim 26, with the further proviso that the composition does not comprise a nucleic acid molecule that is complementary to a variant TP53 mRNA.