Gaudet, Mia M., Kirchhoff, Tomas ORCID: 0000-0002-9055-2364, Green, Todd, Vijai, Joseph, Korn, Joshua M., Guiducci, Candace, Segre, Ayellet V., McGee, Kate, McGuffog, Lesley, Kartsonaki, Christiana, Morrison, Jonathan, Healey, Sue, Sinilnikova, Olga M., Stoppa-Lyonnet, Dominique, Mazoyer, Sylvie ORCID: 0000-0002-2135-0160, Gauthier-Villars, Marion, Sobol, Hagay, Longy, Michel, Frenay, Marc, Hogervorst, Frans B. L., Rookus, Matti A., Collee, J. Margriet, Hoogerbrugge, Nicoline ORCID: 0000-0003-2393-8141, van Roozendaal, Kees E. P., Piedmonte, Marion, Rubinstein, Wendy, Nerenstone, Stacy, Van Le, Linda, Blank, Stephanie V., Caldes, Trinidad, de la Hoya, Miguel ORCID: 0000-0002-8113-1410, Nevanlinna, Heli ORCID: 0000-0002-0916-2976, Aittomaki, Kristiina, Lazaro, Conxi, Blanco, Ignacio ORCID: 0000-0002-7414-7481, Arason, Adalgeir, Johannsson, Oskar T., Barkardottir, Rosa B., Devilee, Peter, Olopade, Olofunmilayo I., Neuhausen, Susan L., Wang, Xianshu, Fredericksen, Zachary S., Peterlongo, Paolo ORCID: 0000-0001-6951-6855, Manoukian, Siranoush, Barile, Monica, Viel, Alessandra ORCID: 0000-0003-2804-0840, Radice, Paolo ORCID: 0000-0001-6298-4111, Phelan, Catherine M., Narod, Steven, Rennert, Gad, Lejbkowicz, Flavio, Flugelman, Anath, Andrulis, Irene L., Glendon, Gord, Ozcelik, Hilmi, Toland, Amanda E., Montagna, Marco, D'Andrea, Emma, Friedman, Eitan, Laitman, Yael, Borg, Ake, Beattie, Mary, Ramus, Susan J., Domchek, Susan M., Nathanson, Katherine L., Rebbeck, Tim, Spurdle, Amanda B., Chen, Xiaoqing, Holland, Helene, John, Esther M., Hopper, John L., Buys, Saundra S., Daly, Mary B., Southey, Melissa C., Terry, Mary Beth, Tung, Nadine, Hansen, Thomas V. Overeem, Nielsen, Finn C., Greene, Mark I., Mai, Phuong L., Osorio, Ana ORCID: 0000-0001-8124-3984, Duran, Mercedes, Andres, Raquel, Benitez, Javier, Weitzel, Jeffrey N., Garber, Judy, Hamann, Ute, Peock, Susan, Cook, Margaret, Oliver, Clare, Frost, Debra, Platte, Radka, Evans, D. Gareth, Lalloo, Fiona, Eeles, Ros, Izatt, Louise, Walker, Lisa, Eason, Jacqueline, Barwell, Julian, Godwin, Andrew K., Schmutzler, Rita K., Wappenschmidt, Barbara, Engert, Stefanie, Arnold, Norbert ORCID: 0000-0003-4523-8808, Gadzicki, Dorothea, Dean, Michael, Gold, Bert, Klein, Robert J., Couch, Fergus J., Chenevix-Trench, Georgia ORCID: 0000-0002-1878-2587, Easton, Douglas F., Daly, Mark J., Antoniou, Antonis C., Altshuler, David M. and Offit, Kenneth (2010). Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer. PLoS Genet., 6 (10). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1553-7404

Full text not available from this repository.

Abstract

The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (, 40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (lambda) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values, 10 25 and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, p = 3: 8 x 10(-5)) and for rs311499 was 0.72 (95% CI 0.61-0.85, p = 6: 6 x 10(-5)). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, p = 1: 2 x 10(-8)). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Gaudet, Mia M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kirchhoff, TomasUNSPECIFIEDorcid.org/0000-0002-9055-2364UNSPECIFIED
Green, ToddUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vijai, JosephUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Korn, Joshua M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guiducci, CandaceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Segre, Ayellet V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McGee, KateUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McGuffog, LesleyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kartsonaki, ChristianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morrison, JonathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Healey, SueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sinilnikova, Olga M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoppa-Lyonnet, DominiqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mazoyer, SylvieUNSPECIFIEDorcid.org/0000-0002-2135-0160UNSPECIFIED
Gauthier-Villars, MarionUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sobol, HagayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Longy, MichelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frenay, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hogervorst, Frans B. L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rookus, Matti A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Collee, J. MargrietUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoogerbrugge, NicolineUNSPECIFIEDorcid.org/0000-0003-2393-8141UNSPECIFIED
van Roozendaal, Kees E. P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Piedmonte, MarionUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rubinstein, WendyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nerenstone, StacyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Le, LindaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blank, Stephanie V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caldes, TrinidadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de la Hoya, MiguelUNSPECIFIEDorcid.org/0000-0002-8113-1410UNSPECIFIED
Nevanlinna, HeliUNSPECIFIEDorcid.org/0000-0002-0916-2976UNSPECIFIED
Aittomaki, KristiinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lazaro, ConxiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blanco, IgnacioUNSPECIFIEDorcid.org/0000-0002-7414-7481UNSPECIFIED
Arason, AdalgeirUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Johannsson, Oskar T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barkardottir, Rosa B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Devilee, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olopade, Olofunmilayo I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neuhausen, Susan L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, XianshuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fredericksen, Zachary S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peterlongo, PaoloUNSPECIFIEDorcid.org/0000-0001-6951-6855UNSPECIFIED
Manoukian, SiranoushUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barile, MonicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Viel, AlessandraUNSPECIFIEDorcid.org/0000-0003-2804-0840UNSPECIFIED
Radice, PaoloUNSPECIFIEDorcid.org/0000-0001-6298-4111UNSPECIFIED
Phelan, Catherine M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Narod, StevenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rennert, GadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lejbkowicz, FlavioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Flugelman, AnathUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andrulis, Irene L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Glendon, GordUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ozcelik, HilmiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toland, Amanda E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Montagna, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
D'Andrea, EmmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Friedman, EitanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laitman, YaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borg, AkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beattie, MaryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramus, Susan J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Domchek, Susan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nathanson, Katherine L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rebbeck, TimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spurdle, Amanda B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, XiaoqingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holland, HeleneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
John, Esther M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hopper, John L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buys, Saundra S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Daly, Mary B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Southey, Melissa C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Terry, Mary BethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tung, NadineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hansen, Thomas V. OvereemUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nielsen, Finn C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Greene, Mark I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mai, Phuong L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Osorio, AnaUNSPECIFIEDorcid.org/0000-0001-8124-3984UNSPECIFIED
Duran, MercedesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andres, RaquelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benitez, JavierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weitzel, Jeffrey N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garber, JudyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamann, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peock, SusanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cook, MargaretUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oliver, ClareUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frost, DebraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Platte, RadkaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Evans, D. GarethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lalloo, FionaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eeles, RosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Izatt, LouiseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walker, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eason, JacquelineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barwell, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Godwin, Andrew K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmutzler, Rita K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wappenschmidt, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engert, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arnold, NorbertUNSPECIFIEDorcid.org/0000-0003-4523-8808UNSPECIFIED
Gadzicki, DorotheaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dean, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gold, BertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, Robert J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Couch, Fergus J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chenevix-Trench, GeorgiaUNSPECIFIEDorcid.org/0000-0002-1878-2587UNSPECIFIED
Easton, Douglas F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Daly, Mark J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Antoniou, Antonis C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altshuler, David M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Offit, KennethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-496208
DOI: 10.1371/journal.pgen.1001183
Journal or Publication Title: PLoS Genet.
Volume: 6
Number: 10
Date: 2010
Publisher: PUBLIC LIBRARY SCIENCE
Place of Publication: SAN FRANCISCO
ISSN: 1553-7404
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
BRCA2 MUTATION CARRIERS; RECURRENT BRCA1; SUSCEPTIBILITY; RISK; PREDISPOSITION; ASSOCIATION; PHENOTYPE; FREQUENCY; MODELMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/49620

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