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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 2014,14 Sep 2015

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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 hypermutated 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 760 patients 12 of men with hypermutated advanced prostate cancers. Using a targeted deep sequencing assay that includes intronic and flanking regions we discovered DNA mismatch repair MMR gene mutations in all hypermutated 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 hypermutated 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. During the next year we plan to focus work on aims 2 and 3, which will involve testing responsiveness of hypermutated prostate tumors to genotoxic therapies and developing clinical testing approaches to identify hypermutated prostate cancers.


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