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Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer

Gaudet, Mia M.; Kirchhoff, Tomas; Green, Todd; Vijai, Joseph; Korn, Joshua M.; Guiducci, Candace; Segre, Ayellet V.; McGee, Kate; McGuffog, Lesley and Kartsonaki, Christiana, et al. (2010) In PLoS Genetics 6(10).
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... (More)
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. (Less)
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PLoS Genetics
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6
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10
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Public Library of Science
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1553-7404
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10.1371/journal.pgen.1001183
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English
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@article{a8f6b683-65d8-4631-85a9-327a215a6d29,
  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&lt;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.},
  author       = {Gaudet, Mia M. and Kirchhoff, Tomas and Green, Todd and Vijai, Joseph and Korn, Joshua M. and Guiducci, Candace and Segre, Ayellet V. and McGee, Kate and McGuffog, Lesley and Kartsonaki, Christiana and Morrison, Jonathan and Healey, Sue and Sinilnikova, Olga M. and Stoppa-Lyonnet, Dominique and Mazoyer, Sylvie and Gauthier-Villars, Marion and Sobol, Hagay and Longy, Michel and Frenay, Marc and Hogervorst, Frans B. L. and Rookus, Matti A. and Collee, J. Margriet and Hoogerbrugge, Nicoline and van Roozendaal, Kees E. P. and Piedmonte, Marion and Rubinstein, Wendy and Nerenstone, Stacy and Van Le, Linda and Blank, Stephanie V. and Caldes, Trinidad and de la Hoya, Miguel and Nevanlinna, Heli and Aittomaki, Kristiina and Lazaro, Conxi and Blanco, Ignacio and Arason, Adalgeir and Johannsson, Oskar T. and Barkardottir, Rosa B. and Devilee, Peter and Olopade, Olofunmilayo I. and Neuhausen, Susan L. and Wang, Xianshu and Fredericksen, Zachary S. and Peterlongo, Paolo and Manoukian, Siranoush and Barile, Monica and Viel, Alessandra and Radice, Paolo and Phelan, Catherine M. and Narod, Steven and Rennert, Gad and Lejbkowicz, Flavio and Flugelman, Anath and Andrulis, Irene L. and Glendon, Gord and Ozcelik, Hilmi and Toland, Amanda E. and Montagna, Marco and D'Andrea, Emma and Friedman, Eitan and Laitman, Yael and Borg, Åke and Beattie, Mary and Ramus, Susan J. and Domchek, Susan M. and Nathanson, Katherine L. and Rebbeck, Tim and Spurdle, Amanda B. and Chen, Xiaoqing and Holland, Helene and John, Esther M. and Hopper, John L. and Buys, Saundra S. and Daly, Mary B. and Southey, Melissa C. and Terry, Mary Beth and Tung, Nadine and Hansen, Thomas V. Overeem and Nielsen, Finn C. and Greene, Mark I. and Mai, Phuong L. and Osorio, Ana and Duran, Mercedes and Andres, Raquel and Benitez, Javier and Weitzel, Jeffrey N. and Garber, Judy and Hamann, Ute and Peock, Susan and Cook, Margaret and Oliver, Clare and Frost, Debra and Platte, Radka and Evans, D. Gareth and Lalloo, Fiona and Eeles, Ros and Izatt, Louise and Walker, Lisa and Eason, Jacqueline and Barwell, Julian and Godwin, Andrew K. and Schmutzler, Rita K. and Wappenschmidt, Barbara and Engert, Stefanie and Arnold, Norbert and Gadzicki, Dorothea and Dean, Michael and Gold, Bert and Klein, Robert J. and Couch, Fergus J. and Chenevix-Trench, Georgia and Easton, Douglas F. and Daly, Mark J. and Antoniou, Antonis C. and Altshuler, David M. and Offit, Kenneth},
  issn         = {1553-7404},
  language     = {eng},
  number       = {10},
  publisher    = {Public Library of Science},
  series       = {PLoS Genetics},
  title        = {Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer},
  url          = {http://dx.doi.org/10.1371/journal.pgen.1001183},
  volume       = {6},
  year         = {2010},
}