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Novel markers for detecting microsatellite instability in cancer and determining synthetic lethality with inhibition of the dna base excision repair pathway

A microsatellite, cancer technology, applied in the field of mismatch repair deficient tumors, which can solve problems such as short reading

Inactive Publication Date: 2015-02-25
VLAAMS INTERUNIVERSITAIR INST VOOR BIOTECHNOLOGIE VZW +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although cheaper, these techniques utilize shorter reads and cannot be used to detect microsatellite instability on Bethesda's standard line of machines

Method used

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  • Novel markers for detecting microsatellite instability in cancer and determining synthetic lethality with inhibition of the dna base excision repair pathway
  • Novel markers for detecting microsatellite instability in cancer and determining synthetic lethality with inhibition of the dna base excision repair pathway
  • Novel markers for detecting microsatellite instability in cancer and determining synthetic lethality with inhibition of the dna base excision repair pathway

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0337] Example 1. Whole-genome sequencing of MMR-deficient endometrial tumors

[0338] To select MMR-deficient tumors for whole-genome sequencing, standard diagnostic tests were used, including immunohistochemistry for MMR proteins (MLH1, MSH2, and MSH6), assessment of microsatellite instability (MSI) with the extended Bethesda panel (Pinol et al , 2005) and profiling of the methylation profile of the MLH1 promoter. The results of immunohistochemistry and MLH1 promoter hypermethylation are shown as the first 3 rows in Table 9. The series recommended by the international MSI evaluation guidelines (i.e., the revised Bethesda series (Boland et al., 1998; Dietmaier et al., 1997)) was used at 10 markers containing mononucleotide or dinucleotide repeats (2 and 8 markers, respectively). Microsatellite instability (MSI) status was analyzed at different loci. PCR amplification was performed in two pentaplexes: multiplex A (BAT25, BAT26, D5S346, D17S250, D2S123) and multiplex B (BAT40...

Embodiment 2

[0350] Example 2. Patterns of somatic mutations in MSH6-deficient hypervariants

[0351] Studies in model organisms and cell lines have revealed that somatic mutations arising due to MMR deficiency involve in most cases affecting microsatellite sequences (dinucleotides with a minimum length of 6 bases and at least two repeat units to Hexanucleotide repeats) and homopolymers (mononucleotide repeats with a minimum length of 6 bases) indels (insertions / deletions) (Ellegren, 2004). To test this hypothesis, we stratified the genome into four distinct categories with the following definitions:

[0352] - Microsatellite region: di-, tri-, tetra-, penta- or hexanucleotide repeats consisting of at least two repeat units and having a minimum length of 6 bases.

[0353] - Homopolymeric regions: mononucleotide repeats with a minimum length of 6 bases.

[0354] - Short homopolymeric regions: mononucleotide repeats of 3, 4 or 5 bases in length.

[0355] - Non-repeated region: every base ...

Embodiment 3

[0365] Example 3. Exome Sequencing of Mismatch Repair Deficient and Competent Tumors and Their Matched Normal Samples

[0366] We selected 10 additional MMR deficient EM and CRC tumors and 4 MMR competent tumors characterized by deficiency of MLH1, MSH2 or MSH6 (Table 9, Table 13). Therefore, a total of 14 tumor-normal pairs were collected for exome sequencing, including 11 endometrial tumors (EM) and their matched germline samples and 3 colorectal tumors (CRC) and their matched germline samples. Yes. All tumors were primary, chemotherapy-naïve tumors. Tumor DNA was derived from fresh-frozen tumor tissue, whereas matched germline DNA for these samples was extracted from peripheral blood leukocytes. Detailed clinical information for all these samples is listed in Table 13. In addition, 5 MMR-deficient primary endometrial tumor cell lines were included in the analysis, bringing a total of 16 MMR-deficient tumor samples.

[0367] Table 13. Clinical Information for Additional ...

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Abstract

The present application relates to the field of cancer, particularly to mismatch repair (MMR-)deficient tumors. New markers are presented herein that have a high sensitivity to detect whether a tumor is mismatch repair deficient or not. The markers are particularly mutations in microsatellite regions. Accordingly, methods are provided for diagnosing microsatellite instability of a tumor, comprising determining the presence of these markers. Further, kits are provided to detect the presence of these markers (or subsets thereof) in a sample.

Description

technical field [0001] The present application relates to the field of cancer, especially mismatch repair (MMR-) deficient tumors. This article provides new markers with high sensitivity for detecting whether a tumor is mismatch repair deficient. The markers are especially mutations in microsatellite regions. Accordingly, there is provided a method for diagnosing microsatellite instability in a tumor comprising determining the presence of these markers. In addition, kits are provided to detect the presence of these markers (or subsets thereof) in a sample. [0002] Interestingly, mutations preferentially affect double-strand break (DSB) repair through the homologous recombination (HR) pathway, and DSB repair is functionally impaired in MMR-deficient tumors. It is shown herein that these tumors are sensitive to the induction of single-strand breaks by pharmacological inhibition of the enzyme poly ADP-ribose polymerase (PARP inhibition). Therefore, based on the synthetic let...

Claims

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Application Information

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IPC IPC(8): C12Q1/68
CPCC12Q2600/156C12Q2600/154C12Q1/6886C12Q2600/106A61P35/00A61P35/02A61P43/00C12Q2600/158C12Q2600/136C12Q2600/112
Inventor D·兰布雷彻特
Owner VLAAMS INTERUNIVERSITAIR INST VOOR BIOTECHNOLOGIE VZW
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