A diagnostic agent for identifying melanoma molecular subtype classification and application thereof

Abstract

The application relates to the field of biomedical technology, and discloses a diagnostic agent for identifying melanoma molecular subtype typing and application, wherein the diagnostic agent comprises a first antibody specifically combined with a SOX10 protein and a second antibody specifically combined with an EGR1 protein; the diagnostic agent can be applied to preparation of a diagnostic product for evaluating the prognostic effect of a melanoma patient, preparation of a diagnostic product for predicting the treatment sensitivity of melanoma to a BRAF inhibitor, and preparation of a diagnostic product for guiding an individualized treatment scheme of melanoma. The diagnostic agent for melanoma molecular subtype typing can be directly transformed into clinical practice, and can assist in realizing real individualized treatment.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to a diagnostic agent and its application for identifying molecular subtypes of melanoma. Background Technology

[0002] Melanoma is a highly malignant and heterogeneous malignant tumor, among which BRAF V600E This is the most common driver gene mutation. Although BRAF inhibitors (such as vemurafenib) are widely used in clinical practice, patient efficacy varies significantly, and primary and acquired drug resistance in tumors is very common. It is currently believed that this resistance is closely related to the existence of cellular subpopulations within tumors with distinct molecular characteristics and malignant potential.

[0003] However, current clinical techniques lack reliable biomarkers that can effectively identify these subgroups with high risk of metastasis and drug resistance. Traditional clinicopathological indicators (such as ulceration and Breslow depth) and single molecular markers are insufficient to accurately predict individual patient response to BRAF inhibitors and their long-term prognosis. Therefore, there is an urgent need in this field for a biomarker capable of effectively identifying BRAF... V600E A new technology for precise molecular subtyping of mutant melanoma aims to effectively differentiate patient subgroups at different risks before treatment, thereby providing crucial evidence for prognostic assessment and individualized treatment decisions. Summary of the Invention

[0004] The purpose of this invention is to address the technical deficiencies in the existing technology by providing a diagnostic agent and its application for identifying molecular subtypes of melanoma.

[0005] The technical solution adopted to achieve the purpose of this invention is:

[0006] A diagnostic agent for identifying molecular subtypes of melanoma, comprising a first antibody that specifically binds to the SOX10 protein and a second antibody that specifically binds to the EGR1 protein.

[0007] In the above technical solution, the SOX10 protein is the human SOX10 protein, and the EGR1 protein is the human EGR1 protein.

[0008] In the above technical solution, the first antibody specifically binds to epitopes 2-29 of the amino acid sequence of human SOX10 protein, the amino acid sequence of which is shown in SEQ ID NO.1; the second antibody specifically binds to epitopes 444-543 of the amino acid sequence of human EGR1 protein, the amino acid sequence of which is shown in SEQ ID NO.2.

[0009] SEQ ID NO.1:

[0010] AEEQDLSEVELSPVGSEEPRCLSPGSAP;

[0011] SEQ ID NO.2:

[0012] SPVATSYPSPVTTSYPSPATTSYPSPVPTSFSSPGSSTYPSPVHSGFPSPSVATTYSSVPPAFPAQVSSFPSSAVTNSFSASTGLSDMTATFSPRTIEIC.

[0013] In the above technical solution, the melanoma molecular subtype is S. LO / E HI subtypes and non-S LO / E HI Subtypes were determined by semi-quantitative H-score analysis of SOX10 and EGR1 protein expression levels. An H-score ≥ 200 was defined as high expression, and H-score < 200 as low expression. Samples with low SOX10 and high EGR1 expression were classified as S. LO / E HI Subtype; S LO / E HI Samples other than the subtype are non-S LO / E HI Subtype.

[0014] In the above technical solution, the diagnostic agent is a reagent kit, and the reagent kit further includes a colorimetric system and a mounting medium.

[0015] Another aspect of the invention includes the use of the diagnostic agent in the preparation of diagnostic articles for assessing the prognostic effects on melanoma patients.

[0016] In the above technical solution, the type will be classified as non-S. LO / E HI Patients with the subtype assessed as having a good prognosis will be classified as S. LO / E HI Patients in the subtype were assessed as having a poor prognosis.

[0017] Another aspect of the invention includes the use of the diagnostic agent in the preparation of diagnostic articles for predicting the therapeutic sensitivity of melanoma to BRAF inhibitors.

[0018] In the above technical solutions, the classification is non-S. LO / E HI Subtype S melanoma is sensitive to BRAF inhibitor therapy. LO / E HISubtypes of melanoma are either resistant to BRAF inhibitors in their primary form or prone to acquired resistance.

[0019] Another aspect of the invention includes the use of the diagnostic agent in the preparation of diagnostic articles for guiding personalized treatment regimens for melanoma.

[0020] In the above technical solutions, the classification is non-S. LO / E HI For patients with subtype S melanoma, the recommended individualized treatment plan is monotherapy with a BRAF inhibitor. LO / E HI For patients with this subtype of melanoma, individualized treatment options include the recommended use of WNT5A inhibitors and BRAF inhibitors.

[0021] Compared with the prior art, the beneficial effects of the present invention are:

[0022] This invention is the first to combine the protein expression of SOX10 and EGR1 for molecular subtyping and treatment guidance of melanoma, with the following beneficial effects:

[0023] 1. Mechanism-driven and highly precise: This invention is not a simple biomarker association, but rather based on a profound understanding of the novel molecular switch mechanism of the "pSOX10-EGR1 inhibitory complex." In melanoma, the functional state of EGR1 is not determined solely by its expression level, but is precisely regulated by its interaction with the lineage transcription factor SOX10 and its phosphorylation state. Specifically, BRAF... V600E The pERK signaling pathway phosphorylates SOX10 (pSOX10), causing it to form an inhibitory complex with EGR1, thereby "hijacking" the pro-differentiation function of EGR1 and inhibiting the expression of differentiation markers such as myelin protein MPZ. However, SOX10 expression in melanoma tissues exhibits significant heterogeneity. In tumor cells with low or absent SOX10 expression, EGR1 function is "de-inhibited," subsequently promoting the transcription of pro-metastatic genes such as WNT5A by binding to guanine-rich sequences, driving tumor invasion and metastasis. LO / E HI Subtypes define tumor populations with high risk of metastasis and drug resistance at the molecular level, with predictive accuracy far exceeding that of single biomarkers;

[0024] 2. Clear clinical guidance significance: This classification can be directly translated into clinical practice. For non-S... LO / E HI For subtype patients, BRAF inhibitor monotherapy may be recommended; for S... LO / E HI For patients with subtypes, this suggests the need for combination therapy with drugs targeting the BRAF / WNT5A pathway, thereby achieving truly individualized treatment. Attached Figure Description

[0025] Figure 1 For BRAF V600E A schematic diagram illustrating the mechanism by which the -pERK signaling pathway regulates the SOX10 / EGR1 molecular switch.

[0026] Figure 2 This is a typical map for detecting the expression of SOX10 and EGR1 proteins in melanoma tissue microarrays using immunohistochemistry.

[0027] Figure 3 For clinical S based on TCGA database LO / E HI Subtype transfer signal analysis. Detailed Implementation

[0028] The present invention will be further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

[0029] Example 1

[0030] A kit comprising a primary antibody that specifically binds to the SOX10 protein (SOX10 antibody), a secondary antibody that specifically binds to the EGR1 protein (EGR1 antibody), PBS buffer, HRP-labeled secondary antibody, ACE chromogenic kit, hematoxylin counterstain, positive control tissue sections, and detailed instructions for use.

[0031] The SOX10 antibody may be the SOX10 antibody of the ZENBIO brand with catalog number R22801, but is not limited to SOX10 antibodies of this brand or other brands other than this catalog number.

[0032] The EGR1 antibody may be the Santa Cruz brand EGR1 antibody with catalog number sc-101033, but is not limited to EGR1 antibodies of this brand or other brands other than this catalog number.

[0033] Example 2

[0034] This embodiment studies the core molecular mechanism upon which the present invention is based, and the results are as follows: Figure 1 As shown, this explains how the expression state of the SOX10 protein determines the function of the transcription factor EGR1, thereby driving BRAF. V600E Mutant melanomas exhibit drastically different cellular fates. This mechanism provides a direct theoretical basis for the "molecular typing method based on SOX10 and EGR1 expression" in this invention.

[0035] The core molecular mechanism is specifically: the oncogenic mutation BRAF. V600EThe downstream signaling molecule ERK1 / 2 is continuously activated and phosphorylated to p-ERK1 / 2. p-ERK1 / 2 can upregulate and activate the transcription factor EGR1. However, the ultimate function of EGR1 does not depend on its expression level, but on its interaction with another transcription factor, SOX10, which is the core hub.

[0036] Left-side pathway (SOX10 sufficiency state): When tumor cells express sufficient SOX10 protein, p-ERK1 / 2 phosphorylates SOX10. p-SOX10 forms a transcriptional repression complex with EGR1, inhibiting the transcription of the myelin protein gene MPZ. This blocks the differentiation of tumor cells into Schwann cells, maintaining them in an undifferentiated, proliferating state. This invention defines this state as a subtype associated with a lower risk of metastasis.

[0037] Right-side pathway (SOX10 deficiency state): When SOX10 protein expression is absent or significantly reduced in tumor cells, EGR1 is released from the repressor complex. Free EGR1 then binds to the promoter of the pro-metastatic gene WNT5A (near the transcription start site TSS), significantly enhancing its transcription and driving tumor cell invasion and distant metastasis. This invention defines this state as a high-metastatic-risk subtype.

[0038] Figure 1 The annotation "BRAF inhibitor resistance" indicates that the aforementioned cellular state of SOX10 deficiency / EGR1 activation / WNT5A overexpression is one of the important mechanisms leading to clinical resistance to BRAF inhibitors. This further confirms that classifying patients by detecting SOX10 and EGR1 can predict their sensitivity to BRAF inhibitor treatment and their risk of resistance.

[0039] Figure 1 This clearly demonstrates that the protein expression levels and intracellular localization of SOX10 and EGR1 are detectable markers determining the activation status of the aforementioned key pathways. Therefore, in situ detection of SOX10 and EGR1 in tumor tissues using methods such as immunohistochemistry can serve the following functions:

[0040] (1) Differentiate subtypes: Accurately classify patients into "SOX10 sufficiency / EGR1 inhibition" (differentiation arrest state, i.e., non-S LO / E HI Subtype) and "SOX10 missing / EGR1 activated" (transition-driven state, i.e. S LO / E HI Two molecular subtypes;

[0041] (2) Prognosis prediction: Clearly identify patient subgroups with high risk of metastasis and potential drug resistance;

[0042] (3) Guiding treatment: It provides direct evidence for the development of differentiated treatment strategies in clinical practice (such as the combined use of WNT5A pathway inhibitors for high metastasis risk subtypes).

[0043] Example 3

[0044] The application of the kit in Example 1 for identifying molecular subtypes of melanoma includes the following steps:

[0045] Step 1: Take paraffin-embedded tissue sections from melanoma patients. After dewaxing, hydration, and antigen retrieval, add the primary antibody (SOX10 antibody) and the secondary antibody (EGR1 antibody) to two melanoma tissue sections from the same patient, respectively, and incubate overnight at 4°C. After washing with PBS, add the corresponding HRP-labeled secondary antibody, perform ACE staining, counterstain with hematoxylin solution, and mount (corresponding to the staining system and mounting medium).

[0046] Step 2: Results are interpreted in a double-blind manner by two or more pathologists. The expression levels of SOX10 and EGR1 are semi-quantitatively determined using the H-Score scoring method (range 0-300). Specifically, H-score = Σ(Pi × I), where Pi represents the proportion of positive cells with a certain intensity, and I represents the staining intensity (values ​​0, 1, 2, 3). The specific calculation method is: H-score = 0 × (percentage of negative cells) + 1 × (percentage of weakly positive cells) + 2 × (percentage of moderately positive cells) + 3 × (percentage of strongly positive cells), with a score range of 0-300. An H-Score ≥ 200 is defined as high expression, and an H-Score < 200 as low expression.

[0047] When SOX10 is low and EGR1 is high, the patient is S LO / E HI Subtypes, in addition to the above expression patterns, classify patients into non-S LO / E HI Subtype.

[0048] Specifically, such as Figure 2 As shown, immunohistochemical (IHC) staining provides a direct comparison of the fundamental differences in protein expression levels between the two key molecular subtypes defined in this invention. Figure 2 The left column shows the SOX10 protein staining results, and the right column shows the EGR1 protein staining results for the corresponding samples. The first row displays "S LO / E HI Typical spectrum of subtype (i.e., high-risk subtype as defined in this invention), the second to fourth rows show "non-S LO / E HITypical patterns of the subtypes (including multiple expression combinations such as high SOX10 / low EGR1) are presented. This parallel design clearly reveals the distinct protein expression patterns of the two subtypes, providing a direct and visual standard basis for the application of the diagnostic reagents and subtyping interpretation.

[0049] As shown in the figure Figure 2 First line: S LO / E HI Typical characteristics of the subtype (high-risk type): In the corresponding tissue region, the immunostaining signal of SOX10 protein is weak to absent, which meets the "low expression" (H-Score<200) characteristic defined in this invention; In the paired section results of the same subtype sample, EGR1 protein shows significant strong positive expression in the nuclear cavity, with a wide staining range and high intensity, which clearly belongs to "high expression" (H-Score≥200).

[0050] This map visualizes the core combination of "low SOX10 expression / high EGR1 expression." This pattern corresponds to the mechanism of this invention ( Figure 1 The “transition-driven state” (SOX10 deficiency leading to EGR1 functional disinhibition) in the study is a direct morphological marker for identifying high-risk patient groups.

[0051] like Figure 2 The last three lines are not S LO / E HI Typical characteristics of the subtype: This type of sample collectively exhibits characteristics similar to S LO / E HI The protein expression trends of the subtypes are opposite, including S HI / E HI S HI / E LO and S LO / E LO Subtypes. Overall, they do not meet the combined criterion of "low SOX10 / high EGR1". These patterns may correspond to different functional states, such as "differentiation arrest" (high SOX10 / low EGR1) or "functional silencing" (both low), but their overall transfer-driven risk is significantly lower than that of S. LO / E HI Subtype.

[0052] Figure 2 This invention demonstrates that the diagnostic agent can not only identify high-risk S... LO / E HI Subtypes can comprehensively cover other potential conditions, avoiding classification blind spots and improving the reliability of clinical applications. Typical staining patterns for each combination provide pathologists with intuitive interpretation references, especially the visualization of H-Score scores (with a threshold of 200), reducing subjective errors and ensuring consistency in classification.

[0053] Example 4

[0054] Clinical relevance validation based on the TCGA database: To validate the clinical prognostic value of the typing method of this invention, data from the Cancer Genome Atlas (TCGA) cutaneous melanoma (SKCM) project were analyzed.

[0055] 1. Data Acquisition and Classification: Data carrying BRAF were selected from the TCGA-SKCM project. V600E A sample of patients with mutations (n=197) was selected. The expression levels of SOX10 and EGR1 genes in each sample were obtained using RNA-seq data. Patients were then classified into SOX10-high / EGR1-low (S0, S1, S2, S3, S4, and S5, using the median SOX10 and EGR1 expression levels as thresholds. HI / E LO Subtypes and SOX10-low / EGR1-high (S LO / E HI )Subtype.

[0056] 2. Transmission signal analysis: S was compared using GSEA, GO analysis, and relative expression level analysis. HI / E LO With S LO / E HI Changes in metastasis-related signaling pathways in subtype patients. The analysis clearly shows that S... LO / E HI The metastatic signal in subtype patients was significantly higher than that in S. HI / E LO Subtype patients.

[0057] Specifically, such as Figure 3 As shown, Figure 3 This refers to S as defined in this invention. LO / E HI Systematic bioinformatics validation of the (SOX10 low expression / EGR1 high expression) molecular subtype. The results, presented in a multi-panel format, confirmed the S... LO / E HI The strong association between subtypes and tumor invasion, metastasis, and potential treatment resistance provides solid data support for the subtyping capabilities and clinical significance of the diagnostic agent.

[0058] like Figure 3 The heatmap (differential gene expression profile) of BRAF A shows the expression of differentially expressed genes in a large number of BRAFs. V600E In samples from patients with mutant melanoma, S LO / E HI Subtype and S as a control HI / E LO Differential gene expression patterns across the entire genome between subtypes.

[0059] Depend on Figure 3 As can be seen in A:

[0060] (1) Subtype-specific gene clusters: The heatmap clearly shows that the two groups of samples have distinctly different gene expression profiles (red represents high expression, and blue represents low expression). The S on the left... LO / E HI The subtype samples clustered and exhibited a series of genes that were co-regulated (red area) and downregulated (blue area), which directly demonstrated S at the transcriptomic level. LO / E HI It is a real biological entity with unique molecular characteristics, rather than a random classification;

[0061] (2) Reliability of subtyping: The significant differentiation of gene expression patterns validates the scientific validity and reproducibility of subtyping based on SOX10 and EGR1 expression levels. This molecular characteristic can serve as a reliable basis for stably distinguishing patient subgroups.

[0062] like Figure 3 Hallmark gene set enrichment analysis (GSEA) of B showed that S was analyzed by GSEA. LO / E HI The subtype significantly enriched (activated) biological processes (Hallmark pathways) compared to the control subtype.

[0063] Depend on Figure 3 As can be seen in B:

[0064] (1) Characteristics of migration and invasion: S LO / E HI The subtype was significantly enriched in the epithelial-mesenchymal transition (EMT) pathway. EMT is a core biological process by which tumor cells acquire the ability to migrate and invade, thereby initiating distant metastasis. This result directly indicates that S LO / E HI The subtype has high functional transfer potential;

[0065] (2) Pro-inflammatory and immune microenvironment: Activation of pathways such as "inflammatory response", "IL6-JAK-STAT3 signaling", and "interferon-γ response" suggests that this subtype may create an immunosuppressive or tumor-promoting microenvironment, which is closely related to tumor immune escape and progression.

[0066] (3) Proliferation and drug resistance related signals: Changes in pathways such as “KRAS signaling pathway activation”, “MYC target”, and “G2 / M checkpoint” are associated with changes in cell proliferation signals and potential chemotherapy / targeted therapy resistance mechanisms.

[0067] In conclusion, Figure 3 The Chinese B-type generatively defines S from the functional pathway level. LO / E HI The malignant nature of the subtype: It is a high-risk subtype that simultaneously possesses high metastatic, pro-inflammatory, and abnormal proliferative characteristics, which explains its poor clinical prognosis.

[0068] like Figure 3 A bubble chart of GO cellular component enrichment analysis for S in cellular components (GO-CC) shows that at the cellular component level, S... LO / E HI Biological processes that lead to significant enrichment of differentially expressed genes in subtypes.

[0069] Depend on Figure 3 As can be seen in C:

[0070] (1) Cell movement and interactions: significantly enriched in processes such as "cell chemotaxis", "cell-substrate adhesion", and "regulation of intercellular adhesion". These processes are directly involved in the migration, invasion, and colonization of tumor cells in metastatic lesions;

[0071] (2) Signal transduction and regulation: The enrichment of “positive regulation of MAPK cascade” and “positive regulation of protein kinase activity” corresponds to the activation of signaling pathways such as KRAS in panel B, revealing the upstream signaling network that drives its malignant phenotype.

[0072] (3) Biological consistency: Panel C supplements and refines the findings of panel B from a more detailed cell biology perspective, jointly depicting S LO / E HI The active motility, communication, and signal transduction states of subtype cells.

[0073] like Figure 3 The enrichment map of the Wnt signaling pathway in D, and the GSEA analysis specifically for the Wnt signaling pathway, show the gene ordering and enrichment fraction (ES) curves in this pathway.

[0074] Depend on Figure 3 As can be seen in D:

[0075] (1) Pathway-specific activation: The ES curve showed a significant peak on the right (NES=1.32, p<0.01), indicating that genes related to the Wnt signaling pathway were activated in the S LO / E HI The subtypes show an overall trend of coordinated upward adjustment;

[0076] (2) Core gene localization: The gene corresponding to the peak is the core driving force for the activation of this pathway. This is the molecular mechanism of "SOX10 deletion leading to EGR1 release, which in turn activates downstream pathways (such as Wnt signaling)" (see instruction manual). Figure 1 This provides direct clinical cohort evidence;

[0077] (3) Mechanism linkage: This result links basic research findings (EGR1 regulates WNT5A) with clinical big data, confirming the universality and importance of this regulatory axis in real patient populations.

[0078] like Figure 3 Validation of expression of key effector genes in E and F (WNT5A and AXL), box plots directly compared S LO / E HI The mRNA expression levels of two key genes, WNT5A and AXL, in the subtype and control subtype.

[0079] like Figure 3 E and F are visible in the middle:

[0080] (1) High expression of WNT5A: As shown in E, S LO / E HI The expression level of WNT5A in the subtype was significantly higher than that in the control subtype (Log2FC=1.67, p<0.01). WNT5A is a classic pro-metastasis and pro-invasion factor, and its high expression is a key indicator of its effectiveness. LO / E HI Direct molecular markers and functional enforcers of subtype transfer phenotypes;

[0081] (2) High expression of AXL: As shown in F, AXL is highly expressed in S LO / E HI It was also significantly upregulated in the subtype (Log2FC=1.48, p<0.01). AXL is a receptor tyrosine kinase, and as a downstream of WNT5A signaling, it is closely related to tumor invasion, drug resistance (especially to targeted therapy), and immunosuppression.

[0082] (3) Diagnostic and therapeutic targets: Verification of WNT5A and AXL expression, on the one hand, for S LO / E HI Subtypes provide easily detectable downstream molecular markers that can serve as auxiliary verification for typing; on the other hand, they themselves are potential drug targets, providing direct target evidence for combination therapy strategies of "BRAF inhibitors combined with WNT5A inhibitors" targeting this high-risk subtype (see the application section of this invention).

[0083] Figure 3 Using the internationally authoritative TCGA clinical database, multi-level bioinformatics analysis irrefutably confirmed that SOX10 / EGR1-based SLO / E HI This subtype corresponds to a melanoma patient subgroup with unique and consistent malignant characteristics in gene expression, signaling pathways, and cellular function. This subtype is enriched with all features associated with poor prognosis (EMT, metastasis, proliferation, drug resistance signals), supporting the "S..." subtype from a big data perspective. LO / E HI The claim that the subtype was assessed as having a poor prognosis. The highly expressed WNT5A and AXL genes specifically provide clear targets for combination therapy for this subtype, validating the claim of "targeting S..." in this invention. LO / E HI The rationale for the clinical application of "combined targeted therapy recommended for subtype patients".

[0084] The above description is only a preferred embodiment of the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A diagnostic agent for identifying molecular subtypes of melanoma, characterized in that, This includes a primary antibody that specifically binds to the SOX10 protein and a secondary antibody that specifically binds to the EGR1 protein; The SOX10 protein is the human SOX10 protein, and the EGR1 protein is the human EGR1 protein; The first antibody specifically binds to epitopes 2-29 of the amino acid sequence of human SOX10 protein, the amino acid sequence of which is shown in SEQ ID NO:1; the second antibody specifically binds to epitopes 444-543 of the amino acid sequence of human EGR1 protein, the amino acid sequence of which is shown in SEQ ID NO:

2. The melanoma molecular subtype is S. LO / E HI subtypes and non-S LO / E HI Subtypes were determined by semi-quantitative H-score analysis of SOX10 and EGR1 protein expression levels. An H-score ≥ 200 was defined as high expression, and H-score < 200 as low expression. Samples with low SOX10 and high EGR1 expression were classified as S. LO / E HI Subtype; S LO / E HI Samples other than the subtype are non-S LO / E HI Subtype.

2. The use of the diagnostic agent as described in claim 1 in the preparation of a diagnostic article for assessing the prognostic effects on melanoma patients.

3. The application as described in claim 2, characterized in that, Classification into non-S LO / E HI Patients with the subtype assessed as having a good prognosis will be classified as S. LO / E HI Patients in the subtype were assessed as having a poor prognosis.

4. The use of the diagnostic agent as described in claim 1 in the preparation of diagnostic articles for predicting the therapeutic sensitivity of melanoma to BRAF inhibitors.

5. The application as described in claim 4, characterized in that, The classification is non-S. LO / E HI Subtype S melanoma is sensitive to BRAF inhibitor therapy. LO / E HI Subtypes of melanoma are either resistant to BRAF inhibitors in their primary form or prone to acquired resistance.

6. The use of the diagnostic agent as described in claim 1 in the preparation of diagnostic articles for guiding personalized treatment of melanoma.

7. The application as described in claim 6, characterized in that, The classification is non-S. LO / E HI For patients with subtype S melanoma, the recommended individualized treatment plan is monotherapy with a BRAF inhibitor. LO / E HI For patients with this subtype of melanoma, individualized treatment options include the recommended use of WNT5A inhibitors and BRAF inhibitors.

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