Common genetic variants and modification of penetrance of BRCA2-associated breast cancer

Mia M. Gaudet, Tomas Kirchhoff, Todd Green, Joseph Vijai, Joshua M. Korn, Candace Guiducci, Ayellet V. Segre, Kate McGee, Lesley McGuffog, Christiana Kartsonaki, Jonathan Morrison, Sue Healey, Olga M. Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Marion Gauthier-Villars, Hagay Sobol, Michel Longy, Marc Frenay, GEMO Study Collaborators, Frans B. L. Hogervorst, Matti a. Rookus, J. Margriet Collee, Nicoline Hoogerbrugge, Kees E. P. van Roozendaal, HEBON Study Collaborators, Marion Piedmonte, Wendy Rubinstein, Stacy Nerenstone, Linda Van Le, Stephanie V. Blank, Trinidad Caldes, Miguel de la Hoya, Heli Nevanlinna, Kristiina Aittomaki, Conxi Lazaro, Ignacio Blanco, Adalgeir Arason, Oskar T. Johannsson, Rosa B. Barkardottir, Peter Devilee, Olofunmilayo I. Olopade, Susan L. Neuhausen, Xianshu Wang, Zachary S. Fredericksen, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Alessandra Viel, Paolo Radice, Catherine M. Phelan, Steven Narod, Gad Rennert, Flavio Lejbkowicz, Anath Flugelman, Irene L. Andrulis, Gord Glendon, Hilmi Ozcelik, OCGN, Amanda E. Toland, Marco Montagna, Emma D'Andrea, Eitan Friedman, Yael Laitman, Ake Borg, Mary Beattie, Susan J. Ramus, Susan M. Domchek, Katherine L. Nathanson, Tim Rebbeck, Spurdle, Amanda B., Chen, Xiaoqing, Helene Holland, kConFab, Esther M. John, John L. Hopper, Saundra s. Buys, Mary B. Daly, Melissa C. Southey, Mary Beth Terry, Nadine Tung, Thomas V. Overeem Hansen, Finn C. Nielsen, Mark H. Greene, Phuong L. Mai, Ana Osorio, Mercedes Duran, Rauel Andres, Javier Benitez, Jeffrey N. Weitzel, Judy Garber, Susan Peock, EMBRACE, Ute Hamann, Margaret Cook, Clare Oliver, Debra Frost, Radka Platte, D. Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Lisa Walker, Jacqueline Eason, Rita K. Schmutzler, Julian Barwell, Andrew K. Godwin, Barbara Wappenschmidt, Stefanie Engert, Norbert Arnold, Bert Gold, Michael Dean, Robert J. Klein, Dorothea Gadzicki, Fergus J. Couch, Chenevix-Trench, Georgia, Douglas F. Easton, Mark J. Daly, Antonis C. Antoniou, David M. Altshuler, Kenneth Offit, Brown, Melissa, Cummings, Margaret and Lakhani, Sunil (2010) Common genetic variants and modification of penetrance of BRCA2-associated breast cancer. PLoS Genetics, 6 10: e1001183-1-e1001183-12. doi:10.1371/journal.pgen.1001183

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Author Mia M. Gaudet
Tomas Kirchhoff
Todd Green
Joseph Vijai
Joshua M. Korn
Candace Guiducci
Ayellet V. Segre
Kate McGee
Lesley McGuffog
Christiana Kartsonaki
Jonathan Morrison
Sue Healey
Olga M. Sinilnikova
Dominique Stoppa-Lyonnet
Sylvie Mazoyer
Marion Gauthier-Villars
Hagay Sobol
Michel Longy
Marc Frenay
GEMO Study Collaborators
Frans B. L. Hogervorst
Matti a. Rookus
J. Margriet Collee
Nicoline Hoogerbrugge
Kees E. P. van Roozendaal
HEBON Study Collaborators
Marion Piedmonte
Wendy Rubinstein
Stacy Nerenstone
Linda Van Le
Stephanie V. Blank
Trinidad Caldes
Miguel de la Hoya
Heli Nevanlinna
Kristiina Aittomaki
Conxi Lazaro
Ignacio Blanco
Adalgeir Arason
Oskar T. Johannsson
Rosa B. Barkardottir
Peter Devilee
Olofunmilayo I. Olopade
Susan L. Neuhausen
Xianshu Wang
Zachary S. Fredericksen
Paolo Peterlongo
Siranoush Manoukian
Monica Barile
Alessandra Viel
Paolo Radice
Catherine M. Phelan
Steven Narod
Gad Rennert
Flavio Lejbkowicz
Anath Flugelman
Irene L. Andrulis
Gord Glendon
Hilmi Ozcelik
Amanda E. Toland
Marco Montagna
Emma D'Andrea
Eitan Friedman
Yael Laitman
Ake Borg
Mary Beattie
Susan J. Ramus
Susan M. Domchek
Katherine L. Nathanson
Tim Rebbeck
Spurdle, Amanda B.
Chen, Xiaoqing
Helene Holland
Esther M. John
John L. Hopper
Saundra s. Buys
Mary B. Daly
Melissa C. Southey
Mary Beth Terry
Nadine Tung
Thomas V. Overeem Hansen
Finn C. Nielsen
Mark H. Greene
Phuong L. Mai
Ana Osorio
Mercedes Duran
Rauel Andres
Javier Benitez
Jeffrey N. Weitzel
Judy Garber
Susan Peock
Ute Hamann
Margaret Cook
Clare Oliver
Debra Frost
Radka Platte
D. Gareth Evans
Fiona Lalloo
Ros Eeles
Louise Izatt
Lisa Walker
Jacqueline Eason
Rita K. Schmutzler
Julian Barwell
Andrew K. Godwin
Barbara Wappenschmidt
Stefanie Engert
Norbert Arnold
Bert Gold
Michael Dean
Robert J. Klein
Dorothea Gadzicki
Fergus J. Couch
Chenevix-Trench, Georgia
Douglas F. Easton
Mark J. Daly
Antonis C. Antoniou
David M. Altshuler
Kenneth Offit
Brown, Melissa
Cummings, Margaret
Lakhani, Sunil
Title Common genetic variants and modification of penetrance of BRCA2-associated breast cancer
Journal name PLoS Genetics   Check publisher's open access policy
ISSN 1553-7390
Publication date 2010-10
Sub-type Article (original research)
DOI 10.1371/journal.pgen.1001183
Open Access Status DOI
Volume 6
Issue 10
Start page e1001183-1
End page e1001183-12
Total pages 12
Editor Gregory S. Barsh
Place of publication San Francisco, CA, U.S.A.
Publisher Public Library of Science
Collection year 2011
Language eng
Formatted 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 (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10−5 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=3.8×10−5) and for rs311499 was 0.72 (95% CI 0.61–0.85, p=6.6×10−5). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18–1.39, p=1.2×10−8). 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 Summary: The risk of breast cancer associated with BRCA2 mutations varies widely. To determine whether common genetic variants modify the penetrance of BRCA2 mutations, we conducted the first genome-wide association study of breast cancer among women with BRCA2 mutations using a two-stage approach. The major finding of the study is that only those loci known to be associated with breast cancer risk in the general population, including FGFR2 (rs2981575), modified BRCA2-associated risk in our high-risk population. Two novel loci, on chromosomes 10 in ZNF365 (rs16917302) and chromosome 20 (rs311499), were shown to modify risk in BRCA2 mutation carriers, although not at a genome-wide level of significance. However, the ZNF365 locus has recently independently been associated with breast cancer risk in sporadic tumors, highlighting the potential significance of this zinc finger-containing gene in breast cancer pathogenesis. Our results indicate that it is unlikely that other common variants have a strong modifying effect on BRCA2 penetrance.
This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
Keyword BRCA2 mutation carriers
Susceptibility genes
Recurrent BRCA1
Q-Index Code CX
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 53 times in Thomson Reuters Web of Science Article | Citations
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Created: Thu, 31 Mar 2011, 11:02:12 EST by Debbie Banks on behalf of Medicine - Royal Brisbane and Women's Hospital