Biallelic BRCA Loss and Homologous Recombination Deficiency in Nonbreast/Ovarian Tumors in Germline BRCA1/2 Carriers.
JCO Precis Oncol
; 7: e2300036, 2023 08.
Article
em En
| MEDLINE
| ID: mdl-37535879
ABSTRACT
PURPOSE:
Breast and ovarian tumors in germline BRCA1/2 carriers undergo allele-specific loss of heterozygosity, resulting in homologous recombination deficiency (HRD) and sensitivity to poly-ADP-ribose polymerase (PARP) inhibitors. This study investigated whether biallelic loss and HRD also occur in primary nonbreast/ovarian tumors that arise in germline BRCA1/2 carriers.METHODS:
A clinically ascertained cohort of BRCA1/2 carriers with a primary nonbreast/ovarian cancer was identified, including canonical (prostate and pancreatic cancers) and noncanonical (all other) tumor types. Whole-exome sequencing or clinical sequencing results (n = 45) were analyzed. A pan-cancer analysis of nonbreast/ovarian primary tumors from germline BRCA1/2 carriers from The Cancer Genome Atlas (TCGA, n = 73) was used as a validation cohort.RESULTS:
Ages of nonbreast/ovarian cancer diagnosis in germline BRCA1/2 carriers were similar to controls for the majority of cancer types. Nine of 45 (20%) primary nonbreast/ovarian tumors from germline BRCA1/2 carriers had biallelic loss of BRCA1/2 in the clinical cohort, and 23 of 73 (32%) in the TCGA cohort. In the combined cohort, 35% and 27% of primary canonical and noncanonical BRCA tumor types, respectively, had biallelic loss. High HRD scores (HRDex > 42) were detected in 81% of tumors with biallelic BRCA loss compared with 22% (P < .001) of tumors without biallelic BRCA loss. No differences in genomic profile, including mutational signatures, mutation spectrum, tumor mutational burden, or microsatellite instability, were found in primary nonbreast/ovarian tumors with or without biallelic BRCA1/2 loss.CONCLUSION:
A proportion of noncanonical primary tumors have biallelic loss and evidence of HRD. Our data suggest that assessment of biallelic loss and HRD could supplement identification of germline BRCA1/2 mutations in selection of patients for platinum or PARP inhibitor therapy.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Ovarianas
/
Proteína BRCA1
Tipo de estudo:
Prognostic_studies
Limite:
Female
/
Humans
Idioma:
En
Revista:
JCO Precis Oncol
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Panamá