1. Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers
- Author
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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, 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., 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 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., MUMC+: DA KG Lab Specialisten (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Institut Català de la Salut, [Hakkaart C, Pearson JF, Wiggins GAR] Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand. [Marquart L] QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. School of Public Health, University of Queensland, Brisbane, Australia. [Dennis J, Barnes DR] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Balmaña J] Hereditary cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Hereditary cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Medicum, Research Programs Unit, Kristiina Aittomäki / Principal Investigator, HUSLAB, Clinicum, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, Pediatrics, Human genetics, Cancer Center Amsterdam, Faculteit Medische Wetenschappen/UMCG, and Medical Oncology
- Subjects
Estrogen-metabolizing enzymes ,Heterozygote ,DNA Copy Number Variations ,Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES] ,Messenger ,Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES] ,Medicine (miscellaneous) ,Expression ,Genetics and Molecular Biology ,Breast Neoplasms ,Breast Neoplasms/genetics ,Genetic polymorphisms ,Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Genomic Structural Variation::DNA Copy Number Variations [PHENOMENA AND PROCESSES] ,General Biochemistry, Genetics and Molecular Biology ,Dna-adducts ,Association ,Mama - Càncer - Propensió ,SDG 3 - Good Health and Well-being ,Other subheadings::Other subheadings::/genetics [Other subheadings] ,Medicine and Health Sciences ,Humans ,Genetic Predisposition to Disease ,Familial breast ,RNA, Messenger ,fenómenos genéticos::variación genética::polimorfismo genético::variación estructural genómica::variaciones del número de copias de ADN [FENÓMENOS Y PROCESOS] ,fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS] ,BRCA2 Protein ,neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES] ,Otros calificadores::Otros calificadores::/genética [Otros calificadores] ,BRCA1 Protein ,Isoform 1a1 sult1a1 ,Sulfotransferase ,BRCA2 Protein/genetics ,Genòmica ,Ovarian ,General Biochemistry ,Mama - Càncer - Aspectes genètics ,RNA ,BRCA1 Protein/genetics ,Female ,3111 Biomedicine ,General Agricultural and Biological Sciences ,Brca1 - 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.
- Published
- 2022