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

5062 Background: 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.[Table: see text]