TY - JOUR

T1 - Non-BRCA1/BRCA2 high-risk familial breast cancers are not associated with a high prevalence of BRCAness

AU - Andersen, Lars v.B.

AU - Larsen, Martin J.

AU - Davies, Helen

AU - Degasperi, Andrea

AU - Nielsen, Henriette Roed

AU - Jensen, Louise A.

AU - Kroeldrup, Lone

AU - Gerdes, Anne Marie

AU - Lænkholm, Anne Vibeke

AU - Kruse, Torben A.

AU - Nik-Zainal, Serena

AU - Thomassen, Mads

N1 - Funding Information: Open access funding provided by University Library of Southern Denmark. This work was supported by funding from the Danish Cancer Society (Journal number R146-A9247-16-S2), Dansk Kræftforskningfond (Journal number 153/1), The Odense University Hospital Fund for Free Research, Faculty of Health Sciences at the University of Southern Denmark, Karen Elise Jensen Foundation, Dagmar Marshalls Foundation, Snedkermester Sophus Jacobsens og hustru Astrid Jacobsens Foundation, Arvid Nilssons Foundation and Overlægerådets Research Foundation. Publisher Copyright: © 2023, The Author(s).

PY - 2023

Y1 - 2023

N2 - Background: 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. Methods: 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. Results: 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. Conclusions: 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.

AB - Background: 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. Methods: 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. Results: 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. Conclusions: 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.

KW - BRCAness

KW - Breast cancer

KW - Hereditary breast cancer

KW - HRDetect

KW - Mutational signatures

KW - Non-BRCA1/BRCA2

KW - Whole genome sequencing

U2 - 10.1186/s13058-023-01655-y

DO - 10.1186/s13058-023-01655-y

M3 - Journal article

C2 - 37316882

AN - SCOPUS:85161843466

VL - 25

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

IS - 1

M1 - 69

ER -