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. Segrè; 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; Frans B.L. Hogervorst; Matti A. Rookus; J. Margriet Collée; Nicoline Hoogerbrugge; Kees E.P. van Roozendaal; Marion Piedmonte; Wendy Rubinstein; Stacy Nerenstone; Linda Van Le; Stephanie V. Blank; Trinidad Caldés; Miguel De la Hoya; Heli Nevanlinna; Kristiina Aittomäki; 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; Amanda B. Spurdle; Xiaoqing Chen; 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 I. Greene; Phuong L. Mai; Ana Osorio; Mercedes Durán; Raquel Andres; Javier Benítez; Jeffrey N. Weitzel; Judy Garber; Ute Hamann; Susan Peock; Margaret Cook; Clare Oliver; Debra Frost; Radka Platte; D. Gareth Evans; Fiona Lalloo; Ros Eeles; Louise Izatt; Lisa Walker; Jacqueline Eason; Julian Barwell; Andrew K. Godwin; Rita K. Schmutzler; Barbara Wappenschmidt; Stefanie Engert; Norbert Arnold; Dorothea Gadzicki; Michael Dean; Bert Gold; Robert J. Klein; Fergus J. Couch; Georgia Chenevix-Trench; Douglas F. Easton; Mark J. Daly; Antonis C. Antoniou; David M. Altshuler; Kenneth Offit

doi:10.1371/journal.pgen.1001183

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. Segrè
, 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
, Frans B.L. Hogervorst

Matti A. Rookus, J. Margriet Collée, Nicoline Hoogerbrugge, Kees E.P. van Roozendaal, Marion Piedmonte, Wendy Rubinstein, Stacy Nerenstone, Linda Van Le, Stephanie V. Blank, Trinidad Caldés, Miguel De la Hoya, Heli Nevanlinna, Kristiina Aittomäki, 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, Amanda B. Spurdle, Xiaoqing Chen, 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 I. Greene, Phuong L. Mai, Ana Osorio, Mercedes Durán, Raquel Andres, Javier Benítez, Jeffrey N. Weitzel, Judy Garber, Ute Hamann, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Radka Platte, D. Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Lisa Walker, Jacqueline Eason, Julian Barwell, Andrew K. Godwin, Rita K. Schmutzler, Barbara Wappenschmidt, Stefanie Engert, Norbert Arnold, Dorothea Gadzicki, Michael Dean, Bert Gold, Robert J. Klein, Fergus J. Couch, Georgia Chenevix-Trench, Douglas F. Easton, Mark J. Daly, Antonis C. Antoniou, David M. Altshuler, Kenneth Offit^*

^*Corresponding author for this work

Albert Einstein College of Medicine
Memorial Sloan-Kettering Cancer Center
Massachusetts Institute of Technology
Massachusetts General Hospital
National Institutes of Health
University of Cambridge
Hospices civils de Lyon
Université de Lyon
INSERM U830
Institut Curie
Aix-Marseille Université
Centre Georges-François Leclerc
Centre Antoine Lacassagne
Netherlands Cancer Institute
Erasmus University Rotterdam
Radboud University Nijmegen
Maastricht University
Roswell Park Cancer Institute
NorthShore University HealthSystem
Institute of Living
University of North Carolina at Chapel Hill
New York University
Hospital Clínico San Carlos de Madrid
Helsinki University Hospital
Institute Catala Oncologia
University of Iceland
Leiden University
The University of Chicago
City of Hope National Med Center
Mayo Clinic Rochester, MN
IRCCS Fondazione Istituto Nazionale per lo studio e la cura dei tumori - Milano
FIRC Institute of Molecular Oncology
IRCCS Istituto Europeo di Oncologia - Milano
IRCCS Centro di Riferimento Oncologico - Aviano PN
Moffitt Cancer Center
Qomen's College Research Institute
Clalit Health Services
University of Toronto
Ohio State University
IRCCS Istituto Oncologico Veneto - Padova
University of Padua
The Gertner Institute
Lund University
University of California at San Francisco
University College London
University of Pennsylvania
Queensland Institute of Medical Research
Cancer Prevention Institute of California
University of Melbourne
University of Utah
Fox Chase Cancer Center
Columbia University
Beth Israel Deaconess Medical Center
University of Copenhagen
Centro Nacional de Investigaciones Oncológicas
University of Valladolid
Hospital Clínico Universitario Lozano Blesa
Harvard University
German Cancer Research Center
Manchester University NHS Foundation Trust
Royal Marsden NHS Foundation Trust
Guy's and St Thomas' NHS Foundation Trust
Oxford University Hospitals NHS Foundation Trust
Nottingham University Hospitals NHS Trust
University Hospitals of Leicester NHS Trust
University of Cologne
Technical University of Munich
University Medical Center Schleswig- Holstein
Hannover Medical School
Peter Maccallum Cancer Centre

Research output: Contribution to journal › Article › peer-review

83 Scopus citations

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.

Original language	English
Article number	e1001183
Pages (from-to)	1-12
Number of pages	12
Journal	PLoS Genetics
Volume	6
Issue number	10
DOIs	https://doi.org/10.1371/journal.pgen.1001183
State	Published - Oct 2010
Externally published	Yes

Funding

Funders	Funder number
National Cancer Institute	P20CA103694

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Access to Document

10.1371/journal.pgen.1001183

Cite this

Gaudet, M. M., Kirchhoff, T., Green, T., Vijai, J., Korn, J. M., Guiducci, C., Segrè, A. V., McGee, K., McGuffog, L., Kartsonaki, C., Morrison, J., Healey, S., Sinilnikova, O. M., Stoppa-Lyonnet, D., Mazoyer, S., Gauthier-Villars, M., Sobol, H., Longy, M., Frenay, M., ... Offit, K. (2010). Common genetic variants and modification of penetrance of BRCA2-associated breast cancer. PLoS Genetics, 6(10), 1-12. Article e1001183. https://doi.org/10.1371/journal.pgen.1001183

@article{84637594431343d78ebf29ee4aec24af,

title = "Common genetic variants and modification of penetrance of BRCA2-associated breast cancer",

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 = "Gaudet, \{Mia M.\} and Tomas Kirchhoff and Todd Green and Joseph Vijai and Korn, \{Joshua M.\} and Candace Guiducci and Segr{\`e}, \{Ayellet V.\} and Kate McGee and Lesley McGuffog and Christiana Kartsonaki and Jonathan Morrison and Sue Healey and Sinilnikova, \{Olga M.\} and Dominique Stoppa-Lyonnet and Sylvie Mazoyer and Marion Gauthier-Villars and Hagay Sobol and Michel Longy and Marc Frenay and Hogervorst, \{Frans B.L.\} and Rookus, \{Matti A.\} and Coll{\'e}e, \{J. Margriet\} and Nicoline Hoogerbrugge and \{van Roozendaal\}, \{Kees E.P.\} and Marion Piedmonte and Wendy Rubinstein and Stacy Nerenstone and \{Van Le\}, Linda and Blank, \{Stephanie V.\} and Trinidad Cald{\'e}s and \{De la Hoya\}, Miguel and Heli Nevanlinna and Kristiina Aittom{\"a}ki and Conxi Lazaro and Ignacio Blanco and Adalgeir Arason and Johannsson, \{Oskar T.\} and Barkardottir, \{Rosa B.\} and Peter Devilee and Olopade, \{Olofunmilayo I.\} and Neuhausen, \{Susan L.\} and Xianshu Wang and Fredericksen, \{Zachary S.\} and Paolo Peterlongo and Siranoush Manoukian and Monica Barile and Alessandra Viel and Paolo Radice and Phelan, \{Catherine M.\} and Steven Narod and Gad Rennert and Flavio Lejbkowicz and Anath Flugelman and Andrulis, \{Irene L.\} and Gord Glendon and Hilmi Ozcelik and Toland, \{Amanda E.\} and Marco Montagna and Emma D'Andrea and Eitan Friedman and Yael Laitman and Ake Borg and Mary Beattie and Ramus, \{Susan J.\} and Domchek, \{Susan M.\} and Nathanson, \{Katherine L.\} and Tim Rebbeck and Spurdle, \{Amanda B.\} and Xiaoqing Chen and Helene Holland 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 Nadine Tung and Hansen, \{Thomas V.Overeem\} and Nielsen, \{Finn C.\} and Greene, \{Mark I.\} and Mai, \{Phuong L.\} and Ana Osorio and Mercedes Dur{\'a}n and Raquel Andres and Javier Ben{\'i}tez and Weitzel, \{Jeffrey N.\} and Judy Garber and Ute Hamann and Susan Peock and Margaret Cook and Clare Oliver and Debra Frost and Radka Platte and Evans, \{D. Gareth\} and Fiona Lalloo and Ros Eeles and Louise Izatt and Lisa Walker and Jacqueline Eason and Julian Barwell and Godwin, \{Andrew K.\} and Schmutzler, \{Rita K.\} and Barbara Wappenschmidt and Stefanie Engert and Norbert Arnold and Dorothea Gadzicki and Michael Dean and Bert Gold and Klein, \{Robert J.\} and Couch, \{Fergus J.\} and Georgia Chenevix-Trench and Easton, \{Douglas F.\} and Daly, \{Mark J.\} and Antoniou, \{Antonis C.\} and Altshuler, \{David M.\} and Kenneth Offit",

year = "2010",

month = oct,

doi = "10.1371/journal.pgen.1001183",

language = "אנגלית",

volume = "6",

pages = "1--12",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "10",

}

Gaudet, MM, Kirchhoff, T, Green, T, Vijai, J, Korn, JM, Guiducci, C, Segrè, AV, McGee, K, McGuffog, L, Kartsonaki, C, Morrison, J, Healey, S, Sinilnikova, OM, Stoppa-Lyonnet, D, Mazoyer, S, Gauthier-Villars, M, Sobol, H, Longy, M, Frenay, M, Hogervorst, FBL, Rookus, MA, Collée, JM, Hoogerbrugge, N, van Roozendaal, KEP, Piedmonte, M, Rubinstein, W, Nerenstone, S, Van Le, L, Blank, SV, Caldés, T, De la Hoya, M, Nevanlinna, H, Aittomäki, K, Lazaro, C, Blanco, I, Arason, A, Johannsson, OT, Barkardottir, RB, Devilee, P, Olopade, OI, Neuhausen, SL, Wang, X, Fredericksen, ZS, Peterlongo, P, Manoukian, S, Barile, M, Viel, A, Radice, P, Phelan, CM, Narod, S, Rennert, G, Lejbkowicz, F, Flugelman, A, Andrulis, IL, Glendon, G, Ozcelik, H, Toland, AE, Montagna, M, D'Andrea, E, Friedman, E, Laitman, Y, Borg, A, Beattie, M, Ramus, SJ, Domchek, SM, Nathanson, KL, Rebbeck, T, Spurdle, AB, Chen, X, Holland, H, John, EM, Hopper, JL, Buys, SS, Daly, MB, Southey, MC, Terry, MB, Tung, N, Hansen, TVO, Nielsen, FC, Greene, MI, Mai, PL, Osorio, A, Durán, M, Andres, R, Benítez, J, Weitzel, JN, Garber, J, Hamann, U, Peock, S, Cook, M, Oliver, C, Frost, D, Platte, R, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Walker, L, Eason, J, Barwell, J, Godwin, AK, Schmutzler, RK, Wappenschmidt, B, Engert, S, Arnold, N, Gadzicki, D, Dean, M, Gold, B, Klein, RJ, Couch, FJ, Chenevix-Trench, G, Easton, DF, Daly, MJ, Antoniou, AC, Altshuler, DM & Offit, K 2010, 'Common genetic variants and modification of penetrance of BRCA2-associated breast cancer', PLoS Genetics, vol. 6, no. 10, e1001183, pp. 1-12. https://doi.org/10.1371/journal.pgen.1001183

TY - JOUR

T1 - Common genetic variants and modification of penetrance of BRCA2-associated breast cancer

AU - Gaudet, Mia M.

AU - Kirchhoff, Tomas

AU - Green, Todd

AU - Vijai, Joseph

AU - Korn, Joshua M.

AU - Guiducci, Candace

AU - Segrè, Ayellet V.

AU - McGee, Kate

AU - McGuffog, Lesley

AU - Kartsonaki, Christiana

AU - Morrison, Jonathan

AU - Healey, Sue

AU - Sinilnikova, Olga M.

AU - Stoppa-Lyonnet, Dominique

AU - Mazoyer, Sylvie

AU - Gauthier-Villars, Marion

AU - Sobol, Hagay

AU - Longy, Michel

AU - Frenay, Marc

AU - Hogervorst, Frans B.L.

AU - Rookus, Matti A.

AU - Collée, J. Margriet

AU - Hoogerbrugge, Nicoline

AU - van Roozendaal, Kees E.P.

AU - Piedmonte, Marion

AU - Rubinstein, Wendy

AU - Nerenstone, Stacy

AU - Van Le, Linda

AU - Blank, Stephanie V.

AU - Caldés, Trinidad

AU - De la Hoya, Miguel

AU - Nevanlinna, Heli

AU - Aittomäki, Kristiina

AU - Lazaro, Conxi

AU - Blanco, Ignacio

AU - Arason, Adalgeir

AU - Johannsson, Oskar T.

AU - Barkardottir, Rosa B.

AU - Devilee, Peter

AU - Olopade, Olofunmilayo I.

AU - Neuhausen, Susan L.

AU - Wang, Xianshu

AU - Fredericksen, Zachary S.

AU - Peterlongo, Paolo

AU - Manoukian, Siranoush

AU - Barile, Monica

AU - Viel, Alessandra

AU - Radice, Paolo

AU - Phelan, Catherine M.

AU - Narod, Steven

AU - Rennert, Gad

AU - Lejbkowicz, Flavio

AU - Flugelman, Anath

AU - Andrulis, Irene L.

AU - Glendon, Gord

AU - Ozcelik, Hilmi

AU - Toland, Amanda E.

AU - Montagna, Marco

AU - D'Andrea, Emma

AU - Friedman, Eitan

AU - Laitman, Yael

AU - Borg, Ake

AU - Beattie, Mary

AU - Ramus, Susan J.

AU - Domchek, Susan M.

AU - Nathanson, Katherine L.

AU - Rebbeck, Tim

AU - Spurdle, Amanda B.

AU - Chen, Xiaoqing

AU - Holland, Helene

AU - John, Esther M.

AU - Hopper, John L.

AU - Buys, Saundra S.

AU - Daly, Mary B.

AU - Southey, Melissa C.

AU - Terry, Mary Beth

AU - Tung, Nadine

AU - Hansen, Thomas V.Overeem

AU - Nielsen, Finn C.

AU - Greene, Mark I.

AU - Mai, Phuong L.

AU - Osorio, Ana

AU - Durán, Mercedes

AU - Andres, Raquel

AU - Benítez, Javier

AU - Weitzel, Jeffrey N.

AU - Garber, Judy

AU - Hamann, Ute

AU - Peock, Susan

AU - Cook, Margaret

AU - Oliver, Clare

AU - Frost, Debra

AU - Platte, Radka

AU - Evans, D. Gareth

AU - Lalloo, Fiona

AU - Eeles, Ros

AU - Izatt, Louise

AU - Walker, Lisa

AU - Eason, Jacqueline

AU - Barwell, Julian

AU - Godwin, Andrew K.

AU - Schmutzler, Rita K.

AU - Wappenschmidt, Barbara

AU - Engert, Stefanie

AU - Arnold, Norbert

AU - Gadzicki, Dorothea

AU - Dean, Michael

AU - Gold, Bert

AU - Klein, Robert J.

AU - Couch, Fergus J.

AU - Chenevix-Trench, Georgia

AU - Easton, Douglas F.

AU - Daly, Mark J.

AU - Antoniou, Antonis C.

AU - Altshuler, David M.

AU - Offit, Kenneth

PY - 2010/10

Y1 - 2010/10

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/78449242326

U2 - 10.1371/journal.pgen.1001183

DO - 10.1371/journal.pgen.1001183

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 21060860

AN - SCOPUS:78449242326

SN - 1553-7390

VL - 6

SP - 1

EP - 12

JO - PLoS Genetics

JF - PLoS Genetics

IS - 10

M1 - e1001183

ER -

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

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