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Characterizing the Hypermutated Subtype of Advanced Prostate Cancer as a Predictive Biomarker for Precision Medicine

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Technical Report,15 Sep 2015,14 Sep 2016

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University of Washington Seattle United States

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The goal of this research is to characterize the mechanisms leading to hyper mutated prostate cancer and to integrate tumor hypermutation status with clinical decision making and therapy to improve the care of men with advanced prostate cancer. We identified 10103 patients 10 of men with hyper mutated advanced prostate cancers. Using a targeted deep sequencing assay that includes intronic and flanking regions we discovered DNA mismatch repair MMRgene mutations in all hyper mutated tumors. Mutations were commonly complex genomic rearrangements in the MSH2 and MSH6 mismatch repair genes. There was loss of the corresponding MMR protein expression in tumor tissue and phenotypic microsatellite instability in every hyper mutated tumor. Our results support that microsatellite instability resulting from loss of function mutations in DNA mismatch repair genes is the major mechanism leading to hypermutation in prostate cancer. We have developed the mSINGS method to detect phenotype microsatellite instability from next-generation sequencing data. This method accurately classified all hyper mutated prostate cancers. We have successfully applied mSINGS to targeted capture assays and to exomedata. We have developed a clinical assay termed MSI plus based on the mSINGS method. We have begun work on PDX models to test responsiveness to specific therapies and have begun to recruit men with prostate cancer in a pilot study to test for MSI and hypermutation. We and others have observed that prostate cancer patients with hyper mutated MSI tumors may be responsive to checkpoint blockade immunotherapy. During the next year we plan to focus work on aim 4, which will involve testing MMR gene mutations using UW-OncoPlex and MSI status using the MSI plus test to identify men with prostate cancer for checkpoint blockage immunotherapy trials.

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