PARP Inhibitor Insensitivity to <i>BRCA1/2</i> Monoallelic Mutations in Microsatellite Instability-High Cancers.

Abstract

To examine the overlap of homologous recombination deficiency (HRD) and microsatellite instability high (MSI-H) status, and to dissect driver versus bystander status of <i>BRCA1/2</i> mutations (<i>BRCAm</i>) in this context. A pan-cancer comprehensive genomic profiling cohort (n = 213,199) was examined for overlap between <i>BRCAm</i> and MSI-H status. <i>BRCA1/2</i> 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 <i>BRCAm</i> and MSI-H are described. HRD and MSI-H phenotypes were generally mutually exclusive events (<i>P</i> < .001). <i>BRCAm</i> 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 <i>BRCAm</i> occurred in the context of MSI-H; however, in prostate cancer, 12.8% of <i>BRCA1</i> and 3.4% of <i>BRCA2</i> alterations co-occurred with MSI-H. In these <i>BRCA</i>-associated cancers, co-occurring <i>BRCAm</i> were generally monoallelic and were not associated with elevated gLOH. Two patients with prostate cancer with co-occurring <i>BRCAm</i> 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 <i>BRCAm</i> prevalence relative to microsatellite-stable tumors, these <i>BRCA1/2</i> mutations were generally monoallelic and were not associated with elevated gLOH. Our findings suggest that most <i>BRCAm</i> coexisting with microsatellite instability are likely bystander events that may not result in sensitivity to poly (ADP-ribose) polymerase inhibitors.