Hakkaart, Christopher, Pearson, John F., Marquart, Louise, Dennis, Joe, Wiggins, George A. R., Barnes, Daniel R., Robinson, Bridget A., Mace, Peter D., Aittomaki, Kristiina, Andrulis, Irene L., Arun, Banu K., Azzollini, Jacopo, Balmana, Judith, Barkardottir, Rosa B., Belhadj, Sami, Berger, Lieke, Blok, Marinus J., Boonen, Susanne E. ORCID: 0000-0002-7824-2080, Borde, Julika, Bradbury, Angela R., Brunet, Joan ORCID: 0000-0003-1945-3512, Buys, Saundra S., Caligo, Maria A., Campbell, Ian, Chung, Wendy K., Claes, Kathleen B. M., Collonge-Rame, Marie-Agnes, 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 ORCID: 0000-0002-5589-3622, Engel, Christoph ORCID: 0000-0002-7247-282X, Evans, D. Gareth, Faust, Ulrike, Feliubadalo, 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., 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, Clementine, Leslie, Goska, Lesueur, Fabienne ORCID: 0000-0001-7404-4549, Mai, Phuong L., Manoukian, Siranoush, Mari, Veronique, 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., Ronlund, 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. and Walker, Logan C. (2022). Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers. Commun. Biol., 5 (1). BERLIN: NATURE PORTFOLIO. ISSN 2399-3642

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Abstract

The risk of germline copy number variants (CNVs) in BRCA1 and BRCA2 pathogenic variant carriers in breast cancer is assessed, with CNVs overlapping SULT1A1 decreasing breast cancer risk in BRCA1 carriers. 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: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Hakkaart, ChristopherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pearson, John F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marquart, LouiseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dennis, JoeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiggins, George A. R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barnes, Daniel R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Robinson, Bridget A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mace, Peter D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aittomaki, KristiinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andrulis, Irene L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arun, Banu K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Azzollini, JacopoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Balmana, JudithUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barkardottir, Rosa B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Belhadj, SamiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berger, LiekeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blok, Marinus J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boonen, Susanne E.UNSPECIFIEDorcid.org/0000-0002-7824-2080UNSPECIFIED
Borde, JulikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bradbury, Angela R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brunet, JoanUNSPECIFIEDorcid.org/0000-0003-1945-3512UNSPECIFIED
Buys, Saundra S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caligo, Maria A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campbell, IanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chung, Wendy K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Claes, Kathleen B. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Collonge-Rame, Marie-AgnesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cook, JackieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cosgrove, CaseyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Couch, Fergus J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Daly, Mary B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dandiker, SitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Davidson, RosemarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de la Hoya, MiguelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Putter, RobinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Delnatte, CapucineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dhawan, MallikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Diez, OrlandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ding, Yuan ChunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Domchek, Susan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Donaldson, AlanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eason, JacquelineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Easton, Douglas F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ehrencrona, HansUNSPECIFIEDorcid.org/0000-0002-5589-3622UNSPECIFIED
Engel, ChristophUNSPECIFIEDorcid.org/0000-0002-7247-282XUNSPECIFIED
Evans, D. GarethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Faust, UlrikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Feliubadalo, LidiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fostira, FlorentiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Friedman, EitanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frone, MeganUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frost, DebraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garber, JudyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gayther, Simon A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gehrig, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gesta, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Godwin, Andrew K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldgar, David E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Greene, Mark H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hahnen, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hake, Christopher R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamann, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hansen, Thomas V. O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hauke, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hentschel, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herold, NatalieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Honisch, EllenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hulick, Peter J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Imyanitov, Evgeny N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Isaacs, ClaudineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Izatt, LouiseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Izquierdo, AngelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jakubowska, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
James, Paul A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Janavicius, RamunasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
John, Esther M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Joseph, VijaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karlan, Beth Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kemp, ZoeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kirk, JudyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Konstantopoulou, IreneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koudijs, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kwong, AvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laitman, YaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lalloo, FionaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lasset, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lautrup, CharlotteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lazaro, ConxiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Legrand, ClementineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leslie, GoskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lesueur, FabienneUNSPECIFIEDorcid.org/0000-0001-7404-4549UNSPECIFIED
Mai, Phuong L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Manoukian, SiranoushUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mari, VeroniqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martens, John W. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McGuffog, LesleyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mebirouk, NouraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meindl, AlfonsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Miller, AustinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Montagna, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moserle, LidiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mouret-Fourme, EmmanuelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Musgrave, HannahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nambot, SophieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nathanson, Katherine L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neuhausen, Susan L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nevanlinna, HeliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yie, Joanne Ngeow YuenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nguyen-Dumont, TuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nikitina-Zake, LieneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Offit, KennethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olah, EdithUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olopade, Olufunmilayo I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Osorio, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ott, Claus-EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Park, Sue K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parsons, Michael T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pedersen, Inge SokildeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peixoto, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perez-Segura, PedroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peterlongo, PaoloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pocza, TimeaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Radice, PaoloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramser, JulianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rantala, JohannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodriguez, Gustavo C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ronlund, KarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenberg, Efraim H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rossing, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmutzler, Rita K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shah, Payal D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sharif, SabaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sharma, PriyankaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Side, Lucy E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simard, JacquesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Singer, Christian F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Snape, KatieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinemann, DorisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoppa-Lyonnet, DominiqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sutter, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tan, Yen YenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teixeira, Manuel R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teo, Soo HwangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomassen, MadsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thull, Darcy L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tischkowitz, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toland, Amanda E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trainer, Alison H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tripathi, VishakhaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tung, NadineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Engelen, KlaartjeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Rensburg, Elizabeth J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vega, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Viel, AlessandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walker, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weitzel, Jeffrey N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wevers, Marike R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chenevix-Trench, GeorgiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spurdle, Amanda B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Antoniou, Antonis C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walker, Logan C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-696604
DOI: 10.1038/s42003-022-03978-6
Journal or Publication Title: Commun. Biol.
Volume: 5
Number: 1
Date: 2022
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 2399-3642
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ESTROGEN-METABOLIZING ENZYMES; ISOFORM 1A1 SULT1A1; DNA-ADDUCTS; GENETIC POLYMORPHISMS; FAMILIAL BREAST; BRCA1; OVARIAN; SULFOTRANSFERASE; EXPRESSION; ASSOCIATIONMultiple languages
Biology; Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69660

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