To examine the overlap of homologous recombination deficiency (HRD) and microsatellite instability high (MSI-H) status, and to dissect driver versus bystander status of mutations () in this context.

A pan-cancer comprehensive genomic profiling cohort (n = 213,199) was examined for overlap between and MSI-H status. variant zygosity was examined and correlated with MSI-H status, tumor mutational burden, and genome-wide loss of heterozygosity (gLOH). Clinical histories of two patients with prostate cancer with co-occurring and MSI-H are described.

HRD and MSI-H phenotypes were generally mutually exclusive events ( < .001). that co-occurred together with high tumor mutational burden or MSI-H were predominantly monoallelic bystander alterations. In breast, ovarian, and pancreatic cancers, very few occurred in the context of MSI-H; however, in prostate cancer, 12.8% of and 3.4% of alterations co-occurred with MSI-H. In these -associated cancers, co-occurring were generally monoallelic and were not associated with elevated gLOH. Two patients with prostate cancer with co-occurring and MSI-H showed resistance to poly (ADP-ribose) polymerase inhibition but sensitivity to subsequent anti-programmed cell death protein 1 therapy.

MSI-H status and HRD are generally mutually exclusive phenomena across cancer types, but may rarely co-occur, especially in prostate cancer. Although MSI-H samples had a higher prevalence relative to microsatellite-stable tumors, these mutations were generally monoallelic and were not associated with elevated gLOH. Our findings suggest that most coexisting with microsatellite instability are likely bystander events that may not result in sensitivity to poly (ADP-ribose) polymerase inhibitors.