Discovery of structural deletions in breast cancer predisposition genes using whole genome sequencing data from > 2000 women of African-ancestry

Zhishan Chen, Xingyi Guo, Jirong Long, Jie Ping, Bingshan Li, Mary Kay Fadden, Thomas U. Ahearn, Daniel O. Stram, Xiao-ou Shu, Guochong Jia, Jonine Figueroa, Robertson Adjei, Lucy Afriyie, Anthony Adjei, Florence Dedey, Verna Vanderpuye, Victoria Okyne, Naomi Ohene Oti, Evelyn Tay, Adu‐aryeeAngela Kenu, Obed Ekpedzor, Marion Alcpaloo, Isaac Boakye, Bernard Arhin, Emmanuel Assimah, Samuel Ka‐chungu, Joseph Oppong, Ernest Osei‐bonsu, Margaret Frempong, Emma Brew Abaidoo, Bridget Nortey Mensah, Samuel Amanama, Prince Agyapong, Debora Boateng, Ansong Thomas Agyei, Richard Opoku, Kofi Owusu Gyimah, Louise Brinton, Michelle Brotzman, Shelley Niwa, Usha Singh, Ann Truelove, Richard Biritwum, Julie R. Palmer, Maureen Sanderson, Christopher A. Haiman, William J. Blot, Montserrat Garcia-closas, Qiuyin Cai, Wei Zheng

Research output: Contribution to journalArticlepeer-review


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 1,340 invasive breast cancer cases and 675 controls of African ancestry. We identified 25 deletions in the intragenic regions of 10 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 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.
Original languageEnglish
JournalHuman Genetics
Early online date27 Aug 2021
Publication statusE-pub ahead of print - 27 Aug 2021


  • structural deletions
  • predisposition genes
  • whole genome sequencing
  • breast cancer
  • African ancestry


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