TY - JOUR
T1 - Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk
AU - KConFab Investigators
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, François
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 - Tischkowitz, Marc
AU - Izatt, Louise
AU - Hodgson, Shirley
AU - Murray, Alex
AU - James, Paul A
PY - 2013
Y1 - 2013
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 × 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 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 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 = 2×10(-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 × 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 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 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 = 2×10(-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 - BRCA1 Protein/genetics
KW - BRCA2 Protein/genetics
KW - Breast Neoplasms/genetics
KW - Female
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Genotype
KW - Heterozygote
KW - Humans
KW - Middle Aged
KW - Mutation
KW - Ovarian Neoplasms/genetics
KW - Polymorphism, Single Nucleotide
KW - Prognosis
KW - Risk Factors
U2 - 10.1371/journal.pgen.1003212
DO - 10.1371/journal.pgen.1003212
M3 - Article
C2 - 23544013
SN - 1553-7390
VL - 9
SP - e1003212
JO - PLoS Genetics
JF - PLoS Genetics
IS - 3
ER -