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

2022; Nature Portfolio; Volume: 5; Issue: 1 Linguagem: Inglês

10.1038/s42003-022-03978-6

2399-3642

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

Cancer Genomics and Diagnostics

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.