Genomic landscape of MSH6-mutated clinically advanced castrate-resistant prostate cancer (mCRPC)

• Published in: Journal of clinical oncology Vol. 39; no. 15_suppl; p. 5062
• Main Authors: Bratslavsky, Gennady, Decker, Brennan, Jacob, Joseph M, Necchi, Andrea, Spiess, Philippe E., Grivas, Petros, Lin, Douglas I., Ramkissoon, Shakti H., Severson, Eric Allan, Huang, Richard S.P., Mata, Douglas A., Madison, Russell, Montesion, Meagan, Gjoerup, Ole, Sokol, Ethan, Pavlick, Dean C., Danziger, Natalie, Ross, Jeffrey S.
• Format: Journal Article
• Language: English
• Published: Wolters Kluwer Health 20.05.2021
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2021.39.15_suppl.5062

5062Background: Loss-of-function genomic alterations (GAs) in MSH6 have been associated with a unique subtype of hypermutated mCRPC that is often microsatellite stable (MSS) and may occur in either a sporadic or familial Lynch Syndrome-like clinical setting. Methods: 5,617 mCRPC cases were sequenced to evaluate all classes of GA using a hybrid capture-based FDA-approved comprehensive genomic profiling (CGP) assay. Tumor mutational burden (TMB) was determined on 0.8 Mb of sequenced DNA and microsatellite instability high (MSI-High) was determined on 95 loci. MSI-low status was not assessed. Results: 78 (1.4%) mCRPC were MSH6mut (Table). MSH6mut mCRPC included 73.1% short variant mutations, 23.1% biallelic deletions, 2.6% genomic rearrangements, and 1.3% multiple GAs/sample. Co-mutation of MSH2 was found in 28% of MSH6mut cases vs. 2% in MSH6wt cases (P <.0001) and was most frequently caused by biallelic co-deletion of both genes (73% of co-mutated cases). MSI-High status was present in 46% of MSH6mut mCRPC, which was significantly greater than the 2% seen in MSH6wt cases (P <.0001). An MMR single nucleotide mutational signature was observed in 65% of MSH6mut cases, compared to 3% MSH6wt cases (P <.0001). Among MSH6mut cases with neither MSI-High nor MMR mutational signature, 87% did not have biallelic loss of MSH6 or any other MMR gene, confirming that monoallelic pathogenic mutations are insufficient to cause the MMR-D phenotype. For subjects whose variants could be classified, 45% (19/42) of pathogenic MSH6 alleles were germline; of these, 58% (11/19) had neither MSI-High nor an MMR single nucleotide signature. MSH6mut cases had fewer TMPRSS2:ERG fusions (P =.01), but harbored significantly higher frequencies of GAs in AR (P =.0002), ATM (P =.04), PIK3CA (P =.0003), APC (P =.005), ERBB2 (P =.001), and CDK6 (p =.046), likely at least partially attributable to the higher TMB in MSH6mutcases (P <.0001). Conclusions: MSH6mut mCRPC is a unique disease that often features a hypermutated genomic signature, although only 46% of cases exhibited MSI-high status. This complex phenotype highlights the potential utility of multiple rather than single biomarkers to understand tumor biology and determine patients who may benefit from immunotherapy.MSH6mut mCRPCMSH6wt mCRPCP ValueNumber of Cases785539Median age (range) years69 (44-89+)67 (38-89+)NSGAs/tumor11.33.9<.0001MSH228%2%<.0001TMPRSS2:ERG19%33%=.01AR32%15%=.0002TP5346%42%NSPTEN39%31%NSBRCA16%1%=.001BRCA29%9%NSATM12%6%=.04RAD2110%11%NSPIK3CA17%7%=.003RB16%6%NSAPC19%9%=.005BRAF3%4%NSERBB26%1%=.001CDK1212%6%NSCDK63%1%=.046MSI High32/69 (46%)2%<.0001MMR Signature65%3%<.0001Median TMB21.32.5<.0001Mean TMB69.73.6<.0001TMB ≥10 mt/Mb67%4%<.0001TMB ≥20 mt/Mb52%2%<.0001PD-L1 Low Positive2/20 (10%)155/1,683 (9%)NSPD-L1 High Positive0/20 (0%)15/1,683 (1%)NS