Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers
Authors: Hakkaart Christopher , Pearson John F. , Marquart Louise , Dennis Joe , Wiggins George A. R. , Barnes Daniel R. , Robinson Bridget A. , Mace Peter D. , Aittomäki Kristiina , Andrulis Irene L. , Arun Banu K. , Azzollini Jacopo , Balmaña Judith , Barkardottir Rosa B. , Belhadj Sami , Berger Lieke , Blok Marinus J. , Boonen Susanne E. , Borde Julika , Bradbury Angela R. , Brunet Joan , Buys Saundra S. , Caligo Maria A. , Campbell Ian , Chung Wendy K. , Claes Kathleen B. M. ,   GEMO Study Collaborators,   EMBRACE Collaborators, Collonge-Rame Marie-Agnès , Cook Jackie , Cosgrove Casey , Couch Fergus J. , Daly Mary B. , Dandiker Sita , Davidson Rosemarie , de la Hoya Miguel , de Putter Robin , Delnatte Capucine , Dhawan Mallika , Diez Orland , Ding Yuan Chun , Domchek Susan M. , Donaldson Alan , Eason Jacqueline , Easton Douglas F. , Ehrencrona Hans , Engel Christoph , Evans D. Gareth , Faust Ulrike , Feliubadaló Lidia , Fostira Florentia , Friedman Eitan , Frone Megan , Frost Debra , Garber Judy , Gayther Simon A. , Gehrig Andrea , Gesta Paul , Godwin Andrew K. , Goldgar David E. , Greene Mark H. , Hahnen Eric , Hake Christopher R. , Hamann Ute , Hansen Thomas V. O. , Hauke Jan , Hentschel Julia , Herold Natalie , Honisch Ellen , Hulick Peter J. , Imyanitov Evgeny N. ,   SWE-BRCA Investigators,   kConFab Investigators,   HEBON Investigators, van Engelen Klaartje , Wevers Marijke R. , Isaacs Claudine , Izatt Louise , Izquierdo Angel , Jakubowska Anna , James Paul A. , Janavicius Ramunas , John Esther M. , Joseph Vijai , Karlan Beth Y. , Kemp Zoe , Kirk Judy , Konstantopoulou Irene , Koudijs Marco , Kwong Ava , Laitman Yael , Lalloo Fiona , Lasset Christine , Lautrup Charlotte , Lazaro Conxi , Legrand Clémentine , Leslie Goska , Lesueur Fabienne , Mai Phuong L. , Manoukian Siranoush , Mari Véronique , Martens John W. M. , McGuffog Lesley , Mebirouk Noura , Meindl Alfons , Miller Austin , Montagna Marco , Moserle Lidia , Mouret-Fourme Emmanuelle , Musgrave Hannah , Nambot Sophie , Nathanson Katherine L. , Neuhausen Susan L. , Nevanlinna Heli , Yie Joanne Ngeow Yuen , Nguyen-Dumont Tu , Nikitina-Zake Liene , Offit Kenneth , Olah Edith , Olopade Olufunmilayo I. , Osorio Ana , Ott Claus-Eric , Park Sue K. , Parsons Michael T. , Pedersen Inge Sokilde , Peixoto Ana , Perez-Segura Pedro , Peterlongo Paolo , Pocza Timea , Radice Paolo , Ramser Juliane , Rantala Johanna , Rodriguez Gustavo C. , Rønlund Karina , Rosenberg Efraim H. , Rossing Maria , Schmutzler Rita K. , Shah Payal D. , Sharif Saba , Sharma Priyanka , Side Lucy E. , Simard Jacques , Singer Christian F. , Snape Katie , Steinemann Doris , Stoppa-Lyonnet Dominique , Sutter Christian , Tan Yen Yen , Teixeira Manuel R. , Teo Soo Hwang , Thomassen Mads , Thull Darcy L. , Tischkowitz Marc , Toland Amanda E. , Trainer Alison H. , Tripathi Vishakha , Tung Nadine , van Engelen Klaartje , van Rensburg Elizabeth J. , Vega Ana , Viel Alessandra , Walker Lisa , Weitzel Jeffrey N. , Wevers Marike R. , Chenevix-Trench Georgia , Spurdle Amanda B. , Antoniou Antonis C. , Walker Logan C. 
Published: October 2022

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.