Non-BRCA1/BRCA2 high-risk familial breast cancers are not associated with a high prevalence of BRCAness

• Published in: Breast cancer research : BCR Vol. 25; no. 1; p. 69
• Main Authors: Andersen, Lars V B, Larsen, Martin J, Davies, Helen, Degasperi, Andrea, Nielsen, Henriette Roed, Jensen, Louise A, Kroeldrup, Lone, Gerdes, Anne-Marie, Lænkholm, Anne-Vibeke, Kruse, Torben A, Nik-Zainal, Serena, Thomassen, Mads
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 14.06.2023; BioMed Central; BMC
• Subjects: Alternative splicing; BRCA1 protein; BRCA2 protein; BRCA2 Protein - genetics; Breast cancer; Breast Neoplasms - epidemiology; Breast Neoplasms - genetics; Cancer; Family medical history; Female; Gene mutations; Genes, BRCA2; Genetic aspects; Genomes; Genomics; Health aspects; Hereditary breast cancer; HRDetect; Humans; Mutation; Mutational signatures; Non-BRCA1/BRCA2; Ovarian cancer; Patients; Prevalence; Tumors; Whole genome sequencing; Non-BRCA1/BRCA2; Mutational signatures; Whole genome sequencing; Breast cancer; Hereditary breast cancer; BRCAness; HRDetect
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/s13058-023-01655-y

Familial breast cancer is in most cases unexplained due to the lack of identifiable pathogenic variants in the BRCA1 and BRCA2 genes. The somatic mutational landscape and in particular the extent of BRCA-like tumour features (BRCAness) in these familial breast cancers where germline BRCA1 or BRCA2 mutations have not been identified is to a large extent unknown. We performed whole-genome sequencing on matched tumour and normal samples from high-risk non-BRCA1/BRCA2 breast cancer families to understand the germline and somatic mutational landscape and mutational signatures. We measured BRCAness using HRDetect. As a comparator, we also analysed samples from BRCA1 and BRCA2 germline mutation carriers. We noted for non-BRCA1/BRCA2 tumours, only a small proportion displayed high HRDetect scores and were characterized by concomitant promoter hypermethylation or in one case a RAD51D splice variant previously reported as having unknown significance to potentially explain their BRCAness. Another small proportion showed no features of BRCAness but had mutationally active tumours. The remaining tumours lacked features of BRCAness and were mutationally quiescent. A limited fraction of high-risk familial non-BRCA1/BRCA2 breast cancer patients is expected to benefit from treatment strategies against homologue repair deficient cancer cells.