Open AccessDiscovery of structural deletions in breast cancer predisposition genes using whole genome sequencing data from > 2000 women of African-ancestry
Author(s) -
Zhishan Chen,
Xingyi Guo,
Jirong Long,
Jie Ping,
Bingshan Li,
Mary Kay Fadden,
Thomas U. Ahearn,
Daniel O. Stram,
XiaoOu Shu,
Guochong Jia,
Jonine D. Figueroa,
Julie R. Palmer,
Maureen Sanderson,
Christopher A. Haiman,
William J. Blot,
Montserrat García-Closas,
Qiuyin Cai,
Zheng Wang
Publication year - 2021
Publication title -
human genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.351
H-Index - 137
eISSN - 1432-1203
pISSN - 0340-6717
DOI - 10.1007/s00439-021-02342-8
Subject(s) - biology , human genetics , genetics , breast cancer , genome , gene , cancer , dna sequencing , computational biology
Single germline nucleotide pathogenic variants have been identified in 12 breast cancer predisposition genes, but structural deletions in these genes remain poorly characterized. We conducted in-depth whole genome sequencing (WGS) in genomic DNA samples obtained from 1340 invasive breast cancer cases and 675 controls of African ancestry. We identified 25 deletions in the intragenic regions of ten established breast cancer predisposition genes based on a consensus call from six state-of-the-art SV callers. Overall, no significant case-control difference was found in the frequency of these deletions. However, 1.0% of cases and 0.3% of controls carried any of the eight putative protein-truncating rare deletions located in BRCA1, BRCA2, CDH1, TP53, NF1, RAD51D, RAD51C and CHEK2, resulting in an odds ratio (OR) of 3.29 (95% CI 0.74-30.16). We also identified a low-frequency deletion in NF1 associated with breast cancer risk (OR 1.93, 95% CI 1.14-3.42). In addition, we detected 56 deletions, including six putative protein-truncating deletions, in suspected breast predisposition genes. This is the first large study to systematically search for structural deletions in breast cancer predisposition genes. Many of the deletions, particularly those resulting in protein truncations, are likely to be pathogenic. Results from this study, if confirmed in future large-scale studies, could have significant implications for genetic testing for this common cancer.