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

Breast Cancer Research

Research

Anne-Marie Gerdes¹  Lone Kroeldrup²  Mads Thomassen³  Torben A. Kruse³  Martin J. Larsen³  Louise A. Jensen³  Lars v. B. Andersen³  Anne-Vibeke Lænkholm⁴  Henriette Roed Nielsen⁵  Helen Davies⁶  Andrea Degasperi⁶  Serena Nik-Zainal⁷ 

[1] Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark;Department of Clinical Genetics, Odense University Hospital, Odense, Denmark;Department of Clinical Genetics, Odense University Hospital, Odense, Denmark;Clinical Genome Center, Department of Clinical Research, University of Southern Denmark, Odense, Denmark;Department of Surgical Pathology, Zealand University Hospital, 4000, Roskilde, Denmark;European Sperm Bank, Copenhagen, Denmark;Hutchison Research Centre, Early Cancer Institute, University of Cambridge, Cambridge Biomedical Campus, CB2 0XZ, Cambridge, UK;Academic Laboratory of Medical Genetics, Lv 6 Addenbrooke’s Treatment Centre, Addenbrooke’s Hospital, CB2 0QQ, Cambridge, UK;Hutchison Research Centre, Early Cancer Institute, University of Cambridge, Cambridge Biomedical Campus, CB2 0XZ, Cambridge, UK;Academic Laboratory of Medical Genetics, Lv 6 Addenbrooke’s Treatment Centre, Addenbrooke’s Hospital, CB2 0QQ, Cambridge, UK;European Sperm Bank, Copenhagen, Denmark;

关键词: Breast cancer;    Hereditary breast cancer;    Non-BRCA1/BRCA2;    Whole genome sequencing;    Mutational signatures;    HRDetect;    BRCAness;   

DOI  :  10.1186/s13058-023-01655-y

 received in 2022-08-09, accepted in 2023-05-09,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundFamilial 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.MethodsWe 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.ResultsWe 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.ConclusionsA 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.

【 授权许可】

CC BY   
© The Author(s) 2023

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