<i>PTEN</i> Loss and <i>BRCA1</i> Promoter Hypermethylation Negatively Predict for Immunogenicity in BRCA-Deficient Ovarian Cancer.

Abstract

Ovarian cancers can exhibit a prominent immune infiltrate, but clinical trials have not demonstrated substantive response rates to immune checkpoint blockade monotherapy. We aimed to understand genomic features associated with immunogenicity in <i>BRCA1/2</i> mutation-associated cancers. Using the Cancer Genome Atlas whole-exome sequencing, methylation, and expression data, we analyzed 66 ovarian cancers with either germline or somatic loss of <i>BRCA1/2</i> and whole-exome sequencing, immunohistochemistry, and CyTOF in 20 ovarian cancers with germline <i>BRCA1/2</i> pathogenic variants from Penn. We found two groups of <i>BRCA1/2</i> ovarian cancers differing in their immunogenicity: (1) 37 tumors significantly enriched for <i>PTEN</i> loss (11, 30%) and <i>BRCA1</i> promoter-hypermethylated (10, 27%; <i>P</i> = .0016) and (2) <i>PTEN</i> wild-type (28 of 29 tumors) cancers, with the latter group having longer overall survival (OS; <i>P</i> = .0186, median OS not reached <i>v</i> median OS = 66.1 months). <i>BRCA1/2</i>-mutant <i>PTEN</i> loss and <i>BRCA1</i> promoter-hypermethylated cancers were characterized by the decreased composition of lymphocytes estimated by gene expression (<i>P</i> = .0030), cytolytic index (<i>P</i> = .034), and cytokine expression but higher homologous recombination deficiency scores (<i>P</i> = .00013). Large-scale state transitions were the primary discriminating feature (<i>P</i> = .001); neither mutational burden nor neoantigen burden could explain differences in immunogenicity. In Penn tumors, <i>PTEN</i> loss and high homologous recombination deficiency cancers exhibited fewer CD3+ (<i>P</i> = .05), CD8+ (<i>P</i> = .012), and FOXP3+ (<i>P</i> = .0087) T cells; decreased PRF1 expression (<i>P</i> = .041); and lower immune costimulatory and inhibitory molecule expression. Our study suggests that within ovarian cancers with genetic loss of <i>BRCA1/2</i> are two subsets exhibiting differential immunogenicity, with lower levels associated with <i>PTEN</i> loss and BRCA hypermethylation. These genomic features of <i>BRCA1/2</i>-associated ovarian cancers may inform considerations around how to optimally deploy immune checkpoint inhibitors in the clinic.