Combined Tumor Sequencing and Case-Control Analyses of RAD51C in Breast Cancer

Abstract Background Loss-of-function variants in RAD51C are associated with familial ovarian cancer, but its role in hereditary breast cancer remains unclear. The aim of this study was to couple breast tumor sequencing with case-control data to clarify the contribution of RAD51C to hereditary breast...

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Published in:JNCI : Journal of the National Cancer Institute 2019-12, Vol.111 (12), p.1332-1338
Main Authors: Li, Na, McInerny, Simone, Zethoven, Magnus, Cheasley, Dane, Lim, Belle W X, Rowley, Simone M, Devereux, Lisa, Grewal, Norah, Ahmadloo, Somayeh, Byrne, David, Lee, Jue Er Amanda, Li, Jason, Fox, Stephen B, John, Thomas, Antill, Yoland, Gorringe, Kylie L, James, Paul A, Campbell, Ian G
Format: Article
Language:English
Subjects:
Adenosine diphosphate
BRCA1 protein
Breast cancer
Confidence intervals
Control data (computers)
Copy number
Deactivation
Deoxyribonucleic acid
DNA
DNA damage
DNA methylation
Estrogens
Genetics
Heredity
Homologous recombination
Homologous recombination repair
Homology
Inactivation
Mutation
Ovarian cancer
Ribose
Sequences
Statistical analysis
Tumors
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Summary:Abstract Background Loss-of-function variants in RAD51C are associated with familial ovarian cancer, but its role in hereditary breast cancer remains unclear. The aim of this study was to couple breast tumor sequencing with case-control data to clarify the contribution of RAD51C to hereditary breast cancer. Methods RAD51C was sequenced in 3080 breast cancer index cases that were negative in BRCA1/2 clinical tests and 4840 population-matched cancer-free controls. Pedigree and pathology data were analyzed. Nine breast cancers and one ovarian cancer from RAD51C variant carriers were sequenced to identify biallelic inactivation of RAD51C, copy number variation, mutational signatures, and the spectrum of somatic mutations in breast cancer driver genes. The promoter of RAD51C was analyzed for DNA methylation. Results A statistically significant excess of loss-of-function variants was identified in 3080 cases (0.4%) compared with 2 among 4840 controls (0.04%; odds ratio = 8.67, 95% confidence interval = 1.89 to 80.52, P< .001), with more than half of the carriers having no personal or family history of ovarian cancer. In addition, the association was highly statistically significant among cases with estrogen-negative (P
ISSN:0027-8874
1460-2105
DOI:10.1093/jnci/djz045