Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

Fergus J. Couch; Xianshu Wang; Lesley McGuffog; Andrew Lee; Curtis Olswold; Karoline B. Kuchenbaecker; Penny Soucy; Zachary Fredericksen; Daniel Barrowdale; Joe Dennis; Mia M. Gaudet; Ed Dicks; Matthew Kosel; Sue Healey; Olga M. Sinilnikova; Adam Lee; Francois Bacot; Daniel Vincent; Frans B. L. Hogervorst; Susan Peock; Dominique Stoppa-Lyonnet; Anna Jakubowska; Paolo Radice; Rita Katharina Schmutzler; Susan M. Domchek; Marion Piedmonte; Christian F. Singer; Eitan Friedman; Mads Thomassen; Thomas V. O. Hansen; Susan L. Neuhausen; Csilla I. Szabo; Ignacio Blanco; Mark H. Greene; Beth Y. Karlan; Judy Garber; Catherine M. Phelan; Jeffrey N. Weitzel; Marco Montagna; Edith Olah; Irene L. Andrulis; Andrew K. Godwin; Drakoulis Yannoukakos; David E. Goldgar; Trinidad Caldes; Heli Nevanlinna; Ana Osorio; Mary Beth Terry; Mary B. Daly; Annemarie van der Hout; kConFab Investigators; SWE-BRCA; Ontario Canc Genetics Network; HEBON; EMBRACE; GEMO Study Collaborators; BCFR; CIMBA

doi:10.1371/journal.pgen.1003212

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

Fergus J. Couch^*, Xianshu Wang, Lesley McGuffog, Andrew Lee, Curtis Olswold, Karoline B. Kuchenbaecker, Penny Soucy, Zachary Fredericksen, Daniel Barrowdale, Joe Dennis, Mia M. Gaudet, Ed Dicks, Matthew Kosel, Sue Healey, Olga M. Sinilnikova, Adam Lee, Francois Bacot, Daniel Vincent, Frans B. L. Hogervorst, Susan PeockDominique Stoppa-Lyonnet, Anna Jakubowska, Paolo Radice, Rita Katharina Schmutzler, Susan M. Domchek, Marion Piedmonte, Christian F. Singer, Eitan Friedman, Mads Thomassen, Thomas V. O. Hansen, Susan L. Neuhausen, Csilla I. Szabo, Ignacio Blanco, Mark H. Greene, Beth Y. Karlan, Judy Garber, Catherine M. Phelan, Jeffrey N. Weitzel, Marco Montagna, Edith Olah, Irene L. Andrulis, Andrew K. Godwin, Drakoulis Yannoukakos, David E. Goldgar, Trinidad Caldes, Heli Nevanlinna, Ana Osorio, Mary Beth Terry, Mary B. Daly, Annemarie van der Hout, kConFab Investigators, SWE-BRCA, Ontario Canc Genetics Network, HEBON, EMBRACE, GEMO Study Collaborators, BCFR, CIMBA

^*Corresponding author for this work

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

223 Citations (Scopus)

327 Downloads (Pure)

Abstract

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

Original language	English
Article number	e1003212
Number of pages	21
Journal	PLoS genetics
Volume	9
Issue number	3
DOIs	https://doi.org/10.1371/journal.pgen.1003212
Publication status	Published - 27-Mar-2013

Keywords

COMMON VARIANTS
SUSCEPTIBILITY ALLELES
GENETIC-VARIANTS
MODIFIERS
INVESTIGATORS
POPULATION
CONSORTIUM
SELECTION
SUBTYPES
ZNF365

Access to Document

10.1371/journal.pgen.1003212Licence: CC BY

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer RiskFinal publisher's version, 2.88 MBLicence: CC BY

Handle.net

Persistent link

Cite this

Couch, F. J., Wang, X., McGuffog, L., Lee, A., Olswold, C., Kuchenbaecker, K. B., Soucy, P., Fredericksen, Z., Barrowdale, D., Dennis, J., Gaudet, M. M., Dicks, E., Kosel, M., Healey, S., Sinilnikova, O. M., Lee, A., Bacot, F., Vincent, D., Hogervorst, F. B. L., ... CIMBA (2013). Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk. PLoS genetics, 9(3), Article e1003212. https://doi.org/10.1371/journal.pgen.1003212

@article{55d1f76b98a74bcbad07d1777c8f4e3c,

title = "Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk",

abstract = "BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.",

keywords = "COMMON VARIANTS, SUSCEPTIBILITY ALLELES, GENETIC-VARIANTS, MODIFIERS, INVESTIGATORS, POPULATION, CONSORTIUM, SELECTION, SUBTYPES, ZNF365",

author = "Couch, {Fergus J.} and Xianshu Wang and Lesley McGuffog and Andrew Lee and Curtis Olswold and Kuchenbaecker, {Karoline B.} and Penny Soucy and Zachary Fredericksen and Daniel Barrowdale and Joe Dennis and Gaudet, {Mia M.} and Ed Dicks and Matthew Kosel and Sue Healey and Sinilnikova, {Olga M.} and Adam Lee and Francois Bacot and Daniel Vincent and Hogervorst, {Frans B. L.} and Susan Peock and Dominique Stoppa-Lyonnet and Anna Jakubowska and Paolo Radice and Schmutzler, {Rita Katharina} and Domchek, {Susan M.} and Marion Piedmonte and Singer, {Christian F.} and Eitan Friedman and Mads Thomassen and Hansen, {Thomas V. O.} and Neuhausen, {Susan L.} and Szabo, {Csilla I.} and Ignacio Blanco and Greene, {Mark H.} and Karlan, {Beth Y.} and Judy Garber and Phelan, {Catherine M.} and Weitzel, {Jeffrey N.} and Marco Montagna and Edith Olah and Andrulis, {Irene L.} and Godwin, {Andrew K.} and Drakoulis Yannoukakos and Goldgar, {David E.} and Trinidad Caldes and Heli Nevanlinna and Ana Osorio and Terry, {Mary Beth} and Daly, {Mary B.} and {van der Hout}, Annemarie and {kConFab Investigators} and SWE-BRCA and {Ontario Canc Genetics Network} and HEBON and EMBRACE and {GEMO Study Collaborators} and BCFR and CIMBA",

year = "2013",

month = mar,

day = "27",

doi = "10.1371/journal.pgen.1003212",

language = "English",

volume = "9",

journal = "PLoS genetics",

issn = "1553-7404",

publisher = "PUBLIC LIBRARY SCIENCE",

number = "3",

}

Couch, FJ, Wang, X, McGuffog, L, Lee, A, Olswold, C, Kuchenbaecker, KB, Soucy, P, Fredericksen, Z, Barrowdale, D, Dennis, J, Gaudet, MM, Dicks, E, Kosel, M, Healey, S, Sinilnikova, OM, Lee, A, Bacot, F, Vincent, D, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Jakubowska, A, Radice, P, Schmutzler, RK, Domchek, SM, Piedmonte, M, Singer, CF, Friedman, E, Thomassen, M, Hansen, TVO, Neuhausen, SL, Szabo, CI, Blanco, I, Greene, MH, Karlan, BY, Garber, J, Phelan, CM, Weitzel, JN, Montagna, M, Olah, E, Andrulis, IL, Godwin, AK, Yannoukakos, D, Goldgar, DE, Caldes, T, Nevanlinna, H, Osorio, A, Terry, MB, Daly, MB, van der Hout, A, kConFab Investigators, SWE-BRCA, Ontario Canc Genetics Network, HEBON, EMBRACE, GEMO Study Collaborators, BCFR & CIMBA 2013, 'Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk', PLoS genetics, vol. 9, no. 3, e1003212. https://doi.org/10.1371/journal.pgen.1003212

TY - JOUR

T1 - Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

AU - Couch, Fergus J.

AU - Wang, Xianshu

AU - McGuffog, Lesley

AU - Lee, Andrew

AU - Olswold, Curtis

AU - Kuchenbaecker, Karoline B.

AU - Soucy, Penny

AU - Fredericksen, Zachary

AU - Barrowdale, Daniel

AU - Dennis, Joe

AU - Gaudet, Mia M.

AU - Dicks, Ed

AU - Kosel, Matthew

AU - Healey, Sue

AU - Sinilnikova, Olga M.

AU - Lee, Adam

AU - Bacot, Francois

AU - Vincent, Daniel

AU - Hogervorst, Frans B. L.

AU - Peock, Susan

AU - Stoppa-Lyonnet, Dominique

AU - Jakubowska, Anna

AU - Radice, Paolo

AU - Schmutzler, Rita Katharina

AU - Domchek, Susan M.

AU - Piedmonte, Marion

AU - Singer, Christian F.

AU - Friedman, Eitan

AU - Thomassen, Mads

AU - Hansen, Thomas V. O.

AU - Neuhausen, Susan L.

AU - Szabo, Csilla I.

AU - Blanco, Ignacio

AU - Greene, Mark H.

AU - Karlan, Beth Y.

AU - Garber, Judy

AU - Phelan, Catherine M.

AU - Weitzel, Jeffrey N.

AU - Montagna, Marco

AU - Olah, Edith

AU - Andrulis, Irene L.

AU - Godwin, Andrew K.

AU - Yannoukakos, Drakoulis

AU - Goldgar, David E.

AU - Caldes, Trinidad

AU - Nevanlinna, Heli

AU - Osorio, Ana

AU - Terry, Mary Beth

AU - Daly, Mary B.

AU - van der Hout, Annemarie

AU - kConFab Investigators

AU - SWE-BRCA

AU - Ontario Canc Genetics Network

AU - HEBON

AU - EMBRACE

AU - GEMO Study Collaborators

AU - BCFR

AU - CIMBA

PY - 2013/3/27

Y1 - 2013/3/27

N2 - BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

AB - BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

KW - COMMON VARIANTS

KW - SUSCEPTIBILITY ALLELES

KW - GENETIC-VARIANTS

KW - MODIFIERS

KW - INVESTIGATORS

KW - POPULATION

KW - CONSORTIUM

KW - SELECTION

KW - SUBTYPES

KW - ZNF365

U2 - 10.1371/journal.pgen.1003212

DO - 10.1371/journal.pgen.1003212

M3 - Article

SN - 1553-7404

VL - 9

JO - PLoS genetics

JF - PLoS genetics

IS - 3

M1 - e1003212

ER -

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

Abstract

Keywords

Access to Document

Handle.net

Fingerprint

Cite this