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.
Original language | English |
---|---|
Article number | 1061 |
Number of pages | 15 |
Journal | Communications Biology |
Volume | 5 |
Issue number | 1 |
DOIs | |
Publication status | Published - 6 Oct 2022 |
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In: Communications Biology, Vol. 5, No. 1, 1061, 06.10.2022.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers
AU - Hakkaart, Christopher
AU - Pearson, John F.
AU - Marquart, Louise
AU - Dennis, Joe
AU - Wiggins, George A.R.
AU - Barnes, Daniel R.
AU - Robinson, Bridget A.
AU - Mace, Peter D.
AU - Aittomäki, Kristiina
AU - Andrulis, Irene L.
AU - Arun, Banu K.
AU - Azzollini, Jacopo
AU - Balmaña, Judith
AU - Barkardottir, Rosa B.
AU - Belhadj, Sami
AU - Berger, Lieke
AU - Blok, Marinus J.
AU - Boonen, Susanne E.
AU - Borde, Julika
AU - Bradbury, Angela R.
AU - Brunet, Joan
AU - Buys, Saundra S.
AU - Caligo, Maria A.
AU - Campbell, Ian
AU - Chung, Wendy K.
AU - Claes, Kathleen B.M.
AU - Collonge-Rame, Marie Agnès
AU - Cook, Jackie
AU - Cosgrove, Casey
AU - Couch, Fergus J.
AU - Daly, Mary B.
AU - Dandiker, Sita
AU - Davidson, Rosemarie
AU - de la Hoya, Miguel
AU - de Putter, Robin
AU - Delnatte, Capucine
AU - Dhawan, Mallika
AU - Diez, Orland
AU - Ding, Yuan Chun
AU - Domchek, Susan M.
AU - Donaldson, Alan
AU - Eason, Jacqueline
AU - Easton, Douglas F.
AU - Ehrencrona, Hans
AU - Engel, Christoph
AU - Evans, D. Gareth
AU - Faust, Ulrike
AU - Feliubadaló, Lidia
AU - Fostira, Florentia
AU - Friedman, Eitan
AU - Frone, Megan
AU - Frost, Debra
AU - Garber, Judy
AU - Gayther, Simon A.
AU - Gehrig, Andrea
AU - Gesta, Paul
AU - Godwin, Andrew K.
AU - Goldgar, David E.
AU - Greene, Mark H.
AU - Hahnen, Eric
AU - Hake, Christopher R.
AU - Hamann, Ute
AU - Hansen, Thomas V.O.
AU - Hauke, Jan
AU - Hentschel, Julia
AU - Herold, Natalie
AU - Honisch, Ellen
AU - Hulick, Peter J.
AU - Imyanitov, Evgeny N.
AU - Isaacs, Claudine
AU - Izatt, Louise
AU - Izquierdo, Angel
AU - Jakubowska, Anna
AU - James, Paul A.
AU - Janavicius, Ramunas
AU - John, Esther M.
AU - Joseph, Vijai
AU - Karlan, Beth Y.
AU - Kemp, Zoe
AU - Kirk, Judy
AU - Konstantopoulou, Irene
AU - Koudijs, Marco
AU - Kwong, Ava
AU - Laitman, Yael
AU - Lalloo, Fiona
AU - Lasset, Christine
AU - Lautrup, Charlotte
AU - Lazaro, Conxi
AU - Legrand, Clémentine
AU - Leslie, Goska
AU - Lesueur, Fabienne
AU - Mai, Phuong L.
AU - Manoukian, Siranoush
AU - Mari, Véronique
AU - Martens, John W.M.
AU - McGuffog, Lesley
AU - Mebirouk, Noura
AU - Meindl, Alfons
AU - Miller, Austin
AU - Montagna, Marco
AU - Moserle, Lidia
AU - Mouret-Fourme, Emmanuelle
AU - Musgrave, Hannah
AU - Nambot, Sophie
AU - Nathanson, Katherine L.
AU - Neuhausen, Susan L.
AU - Nevanlinna, Heli
AU - Yie, Joanne Ngeow Yuen
AU - Nguyen-Dumont, Tu
AU - Nikitina-Zake, Liene
AU - Offit, Kenneth
AU - Olah, Edith
AU - Olopade, Olufunmilayo I.
AU - Osorio, Ana
AU - Ott, Claus Eric
AU - Park, Sue K.
AU - Parsons, Michael T.
AU - Pedersen, Inge Sokilde
AU - Peixoto, Ana
AU - Perez-Segura, Pedro
AU - Peterlongo, Paolo
AU - Pocza, Timea
AU - Radice, Paolo
AU - Ramser, Juliane
AU - Rantala, Johanna
AU - Rodriguez, Gustavo C.
AU - Rønlund, Karina
AU - Rosenberg, Efraim H.
AU - Rossing, Maria
AU - Schmutzler, Rita K.
AU - Shah, Payal D.
AU - Sharif, Saba
AU - Sharma, Priyanka
AU - Side, Lucy E.
AU - Simard, Jacques
AU - Singer, Christian F.
AU - Snape, Katie
AU - Steinemann, Doris
AU - Stoppa-Lyonnet, Dominique
AU - Sutter, Christian
AU - Tan, Yen Yen
AU - Teixeira, Manuel R.
AU - Teo, Soo Hwang
AU - Thomassen, Mads
AU - Thull, Darcy L.
AU - Tischkowitz, Marc
AU - Toland, Amanda E.
AU - Trainer, Alison H.
AU - Tripathi, Vishakha
AU - Tung, Nadine
AU - van Engelen, Klaartje
AU - van Rensburg, Elizabeth J.
AU - Vega, Ana
AU - Viel, Alessandra
AU - Walker, Lisa
AU - Weitzel, Jeffrey N.
AU - Wevers, Marike R.
AU - Chenevix-Trench, Georgia
AU - Spurdle, Amanda B.
AU - Antoniou, Antonis C.
AU - Walker, Logan C.
AU - GEMO Study Collaborators
AU - EMBRACE Collaborators
AU - SWE-BRCA Investigators
AU - kConFab Investigators
AU - HEBON Investigators
N1 - Publisher Copyright: © 2022. The Author(s).
PY - 2022/10/6
Y1 - 2022/10/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85139349547&partnerID=8YFLogxK
U2 - 10.1038/s42003-022-03978-6
DO - 10.1038/s42003-022-03978-6
M3 - Article
C2 - 36203093
AN - SCOPUS:85139349547
SN - 2399-3642
VL - 5
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 1061
ER -