Characterizing the Hypermutated Subtype of Advanced Prostate Cancer as a Predictive Biomarker for Precision Medicine
Technical Report,15 Sep 2016,14 Sep 2017
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 10103 patients 10 percent 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. We have developed the mSINGS method to detect phenotype microsatellite instability from next-generation sequencing data. This method accurately classified hypermutated prostate cancers. We have successfully applied mSINGS to targeted capture assays and to exomedata. We have developed a clinical assay termed MSIplus based on the mSINGS method. We have completed 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 hypermutated MSI tumors may be responsive to checkpoint blockade immunotherapy. During the no-cost extension year we plan to focus work on aim 4, which will involve continued testing of MMR gene mutations using UW-OncoPlex and adapting the MSIplus test to optimize MSI sensitivity to identify men with prostate cancer for checkpoint blockage immunotherapy.
- Medicine and Medical Research