Endometrial Cancers in <i>BRCA1</i> or <i>BRCA2</i> Germline Mutation Carriers: Assessment of Homologous Recombination DNA Repair Defects.

Abstract

Endometrial cancer (EC) is not considered a component of the hereditary breast and ovarian cancer syndrome but can arise in patients with germline <i>BRCA1/2</i> (g<i>BRCA1/2</i>) mutations. Biallelic <i>BRCA1/2</i> alterations are associated with genomic features of homologous recombination DNA repair deficiency (HRD) in cancer. We sought to determine if ECs in g<i>BRCA1/2</i> mutation carriers harbor biallelic alterations and/or features of HRD. Of 769 patients with EC who underwent germline panel testing, 10 pathogenic g<i>BRCA1/2</i> mutation carriers were identified, and their tumor- and normal-derived DNA was subjected to massively parallel sequencing targeting at least 410 cancer-related genes. Three g<i>BRCA1/2</i>-associated ECs were identified in 232 ECs subjected to whole-exome sequencing by The Cancer Genome Atlas. Somatic mutations, copy number alterations, loss of heterozygosity, microsatellite instability (MSI), and genomic HRD features were assessed. Of the 13 patients included who had EC, eight harbored pathogenic g<i>BRCA1</i> mutations and five harbored g<i>BRCA2</i> mutations. Eight (100%) and two (40%) ECs harbored biallelic <i>BRCA1</i> and <i>BRCA2</i> alterations through loss of heterozygosity of the wild-type allele. All ECs harbored somatic <i>TP53</i> mutations. One monoallelic/sporadic g<i>BRCA2</i>-associated EC had <i>MLH1</i> promoter methylation and was MSI high. High large-scale state transition scores, a genomic feature of HRD, were found only in ECs with bi- but not monoallelic <i>BRCA1/2</i> alterations. The Signature Multivariate Analysis HRD signature Sig3 was enriched in biallelic g<i>BRCA1/2</i> ECs, and the three ECs from The Cancer Genome Atlas with <i>BRCA1</i> biallelic alterations subjected to whole-exome sequencing displayed a dominant HRD-related mutational signature 3. A subset of g<i>BRCA1/2</i>-associated ECs harbor biallelic <i>BRCA1/2</i> alterations and genomic features of HRD, which may benefit from homologous recombination-directed treatment regimens. ECs in <i>BRCA2</i> mutation carriers might be sporadic and even MSI high, and may potentially benefit from immune-checkpoint inhibition.