Abstract
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.
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Access to the whole genome sequencing data could be requested by submission of an inquiry to Dr. Wei Zheng.
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Acknowledgements
The authors thank the study participants and research staff for their contributions and support for this project. The study was supported primarily by NIH grant R01CA202981. The data analyses were conducted using the Advanced Computing Center for Research and Education (ACCRE) at Vanderbilt University. The Nashville Breast Health Study and the Southern Community Cohort Study are supported by NIH grants R01CA100374 and U01CA202929, respectively. The GBHS was funded by Intramural Funds of the National Cancer Institute, USA. Samples from the GBHS were processed at the Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Gaithersburg, MD.
Ghana Breast Health Study team: Ghana Statistical Service, Accra, Ghana: Dr Robertson Adjei and Dr Lucy Afriyie. Korle Bu Teaching Hospital, Accra, Ghana: Dr Anthony Adjei, Dr Florence Dedey, Dr Verna Vanderpuye, Victoria Okyne, Naomi Ohene Oti, Evelyn Tay, Dr Adu‐Aryee, Angela Kenu and Obed Ekpedzor. Komfo Anoyke Teaching Hospital, Kumasi, Ghana: Marion Alcpaloo, Isaac Boakye, Bernard Arhin, Emmanuel Assimah, Samuel Ka‐chungu, Dr Joseph Oppong and Dr Ernest Osei‐Bonsu. Peace and Love Hospital, Kumasi, Ghana: Prof Margaret Frempong, Emma Brew Abaidoo, Bridget Nortey Mensah, Samuel Amanama, Prince Agyapong, Debora Boateng, Ansong Thomas Agyei, Richard Opoku and Kofi Owusu Gyimah. National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA: Louise Brinton; Westat, Inc.: Michelle Brotzman, Shelley Niwa, Usha Singh and Ann Truelove. University of Ghana: Prof Richard Biritwum.
Funding
The study was supported primarily by NIH grant R01CA202981.
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Study design: WZ and XG; data analysis: ZC, XG, and JP; data interpretation: JL, QC, X-OS, and WZ; drafting of the manuscript: ZC, XG, and WZ; review of the manuscript: ZC, XG, JL, QC, X-OS, PJR, CAH, MG-C, and WZ; Administrative, technical, or material support: BL, FMK, TUA, SDO, GJ, JF, the GBHS team, PJR, MS, CAH, WJB, MG-C, and WZ.
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Supplementary file3 Supplementary Table 3: List of 40 established and suspected breast cancer predisposition genes included in this study (PDF 20 KB)
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Supplementary file4 Supplementary Table 4: List of 81 SV deletions identified in established and suspected breast cancer predisposition genes (PDF 165 KB)
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Supplementary file5 Supplementary Table 5: Characterization of 25 potential pathogenetic SV deletions identified in established breast cancer predisposition genes (PDF 1554 KB)
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Supplementary file6 Supplementary Table 6: List of SV deletions identified in established predisposition genes with high reciprocal overlap (> 90%) with deletions in gnomAD (PDF 14 KB)
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Supplementary file7 Supplementary Fig 1: SV deletion in the intronic region of the PTEN gene in nine cases. From top to bottom, gene structure; layeredH3K4Me1; DNase clusters; clustered ChIP-seq binding sites; The signals of layer H3K4 methylation from different ENCODE cell lines are shown indifferent colors (JPG 161 KB)
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Chen, Z., Guo, X., Long, J. et al. Discovery of structural deletions in breast cancer predisposition genes using whole genome sequencing data from > 2000 women of African-ancestry. Hum Genet 140, 1449–1457 (2021). https://doi.org/10.1007/s00439-021-02342-8
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DOI: https://doi.org/10.1007/s00439-021-02342-8