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Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers.

Hakkaart, C; Pearson, JF; Marquart, L; Dennis, J; Wiggins, GAR; Barnes, DR; Robinson, BA; Mace, PD; Aittomäki, K; Andrulis, IL; et al. Hakkaart, C; Pearson, JF; Marquart, L; Dennis, J; Wiggins, GAR; Barnes, DR; Robinson, BA; Mace, PD; Aittomäki, K; Andrulis, IL; Arun, BK; Azzollini, J; Balmaña, J; Barkardottir, RB; Belhadj, S; Berger, L; Blok, MJ; Boonen, SE; Borde, J; Bradbury, AR; Brunet, J; Buys, SS; Caligo, MA; Campbell, I; Chung, WK; Claes, KBM; GEMO Study Collaborators; EMBRACE Collaborators; Collonge-Rame, M-A; Cook, J; Cosgrove, C; Couch, FJ; Daly, MB; Dandiker, S; Davidson, R; de la Hoya, M; de Putter, R; Delnatte, C; Dhawan, M; Diez, O; Ding, YC; Domchek, SM; Donaldson, A; Eason, J; Easton, DF; Ehrencrona, H; Engel, C; Evans, DG; Faust, U; Feliubadaló, L; Fostira, F; Friedman, E; Frone, M; Frost, D; Garber, J; Gayther, SA; Gehrig, A; Gesta, P; Godwin, AK; Goldgar, DE; Greene, MH; Hahnen, E; Hake, CR; Hamann, U; Hansen, TVO; Hauke, J; Hentschel, J; Herold, N; Honisch, E; Hulick, PJ; Imyanitov, EN; SWE-BRCA Investigators; kConFab Investigators; HEBON Investigators; Isaacs, C; Izatt, L; Izquierdo, A; Jakubowska, A; James, PA; Janavicius, R; John, EM; Joseph, V; Karlan, BY; Kemp, Z; Kirk, J; Konstantopoulou, I; Koudijs, M; Kwong, A; Laitman, Y; Lalloo, F; Lasset, C; Lautrup, C; Lazaro, C; Legrand, C; Leslie, G; Lesueur, F; Mai, PL; Manoukian, S; Mari, V; Martens, JWM; McGuffog, L; Mebirouk, N; Meindl, A; Miller, A; Montagna, M; Moserle, L; Mouret-Fourme, E; Musgrave, H; Nambot, S; Nathanson, KL; Neuhausen, SL; Nevanlinna, H; Yie, JNY; Nguyen-Dumont, T; Nikitina-Zake, L; Offit, K; Olah, E; Olopade, OI; Osorio, A; Ott, C-E; Park, SK; Parsons, MT; Pedersen, IS; Peixoto, A; Perez-Segura, P; Peterlongo, P; Pocza, T; Radice, P; Ramser, J; Rantala, J; Rodriguez, GC; Rønlund, K; Rosenberg, EH; Rossing, M; Schmutzler, RK; Shah, PD; Sharif, S; Sharma, P; Side, LE; Simard, J; Singer, CF; Snape, K; Steinemann, D; Stoppa-Lyonnet, D; Sutter, C; Tan, YY; Teixeira, MR; Teo, SH; Thomassen, M; Thull, DL; Tischkowitz, M; Toland, AE; Trainer, AH; Tripathi, V; Tung, N; van Engelen, K; van Rensburg, EJ; Vega, A; Viel, A; Walker, L; Weitzel, JN; Wevers, MR; Chenevix-Trench, G; Spurdle, AB; Antoniou, AC; Walker, LC (2022) Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers. Commun Biol, 5 (1). p. 1061. ISSN 2399-3642 https://doi.org/10.1038/s42003-022-03978-6
SGUL Authors: Snape, Katie Mairwen Greenwood

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Abstract

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.

Item Type: Article
Additional Information: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2022
Keywords: GEMO Study Collaborators, EMBRACE Collaborators, SWE-BRCA Investigators, kConFab Investigators, HEBON Investigators
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Journal or Publication Title: Commun Biol
ISSN: 2399-3642
Language: eng
Dates:
DateEvent
6 October 2022Published
12 September 2022Accepted
Publisher License: Creative Commons: Attribution 4.0
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PubMed ID: 36203093
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/114906
Publisher's version: https://doi.org/10.1038/s42003-022-03978-6

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