Endometrial Cancers in BRCA1 or BRCA2 Germline Mutation Carriers: Assessment of Homologous Recombination DNA Repair Defects

Affiliations

PMID: 32914019
PMCID: PMC7446423
DOI: 10.1200/PO.19.00103

Free PMC article

Abstract

Purpose: Endometrial cancer (EC) is not considered a component of the hereditary breast and ovarian cancer syndrome but can arise in patients with germline BRCA1/2 (gBRCA1/2) mutations. Biallelic BRCA1/2 alterations are associated with genomic features of homologous recombination DNA repair deficiency (HRD) in cancer. We sought to determine if ECs in gBRCA1/2 mutation carriers harbor biallelic alterations and/or features of HRD.

Methods: Of 769 patients with EC who underwent germline panel testing, 10 pathogenic gBRCA1/2 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 gBRCA1/2-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.

Results: Of the 13 patients included who had EC, eight harbored pathogenic gBRCA1 mutations and five harbored gBRCA2 mutations. Eight (100%) and two (40%) ECs harbored biallelic BRCA1 and BRCA2 alterations through loss of heterozygosity of the wild-type allele. All ECs harbored somatic TP53 mutations. One monoallelic/sporadic gBRCA2-associated EC had MLH1 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 BRCA1/2 alterations. The Signature Multivariate Analysis HRD signature Sig3 was enriched in biallelic gBRCA1/2 ECs, and the three ECs from The Cancer Genome Atlas with BRCA1 biallelic alterations subjected to whole-exome sequencing displayed a dominant HRD-related mutational signature 3.

Conclusion: A subset of gBRCA1/2-associated ECs harbor biallelic BRCA1/2 alterations and genomic features of HRD, which may benefit from homologous recombination-directed treatment regimens. ECs in BRCA2 mutation carriers might be sporadic and even MSI high, and may potentially benefit from immune-checkpoint inhibition.

Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Karen A. CadooResearch Funding: AstraZeneca (Inst), Syndax (Inst) Travel, Accommodations, Expenses: AstraZenecaNadeem R. Abu-RustumHonoraria: Prime Oncology Research Funding: Stryker/Novadaq (Inst), Olympus (Inst), GRAIL (Inst) Travel, Accommodations, Expenses: Prime OncologyNadeem RiazHonoraria: PeerView Speakers' Bureau: Illumina Research Funding: Bristol-Myers Squibb, Pfizer Travel, Accommodations, Expenses: Varian Medical SystemsMark E. RobsonHonoraria: AstraZeneca Consulting or Advisory Role: McKesson, AstraZeneca Research Funding: AstraZeneca (Inst), Myriad Genetics (Inst), InVitae (Inst), AbbVie (Inst), Tesaro (Inst), Medivation (Inst) Travel, Accommodations, Expenses: AstraZeneca, Pfizer Other Relationship: Research to Practice, Clinical Care Options, Physician Education ResourceRobert A. SoslowSpeakers' Bureau: Ebix/Oakstone Patents, Royalties, Other Intellectual Property: Methods for diagnosis and treatment of endometrial cancer. Assignee: 2015 The Regents of the University of California 8/18/2015 (Inst); Application: Compositions and methods for the diagnosis and treatment of ovarian cancers that are associated with reduced smarca4 gene expression or protein function (Inst); Royalties from published books: Cambridge University Press and Springer PublishingJorge S. Reis-FilhoConsulting or Advisory Role: Roche, Invicro, Ventana Medical Systems, Volition RX, Paige.AI, Goldman Sachs, NovartisBritta WeigeltConsulting or Advisory Role: Roche (I), Invicro (I), Ventana Medical Systems (I), Volition RX (I), Paige.AI (I), Goldman Sachs (I), Novartis (I) No other potential conflicts of interest were reported.