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Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Lookup NU author(s): Dr Anne-Marie Gerdes, Dr Fiona Douglas

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Abstract

Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, ptrend = 1.7 × 10-8 and HR = 1.12, 95% CI: 1.02-1.24, ptrend = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, ptrend = 5 × 10-5 in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers. © 2008 The American Society of Human Genetics.


Publication metadata

Author(s): Antoniou AC, Spurdle AB, Sinilnikova OM, Healey S, Pooley KA, Schmutzler RK, Versmold B, Engel C, Meindl A, Arnold N, Hofmann W, Sutter C, Niederacher D, Deissler H, Caldes T, Kampjarvi K, Nevanlinna H, Simard J, Beesley J, Chen X, Neuhausen SL, Rebbeck TR, Wagner T, Lynch HT, Isaacs C, Weitzel J, Ganz PA, Daly MB, Tomlinson G, Olopade OI, Blum JL, Couch FJ, Peterlongo P, Manoukian S, Barile M, Radice P, Szabo CI, Pereira LHM, Greene MH, Rennert G, Lejbkowicz F, Barnett-Griness O, Andrulis IL, Ozcelik H, Gerdes A-M, Caligo MA, Laitman Y, Kaufman B, Milgrom R, Friedman E, Domchek SM, Nathanson KL, Osorio A, Llort G, Milne RL, Benitez J, Hamann U, Hogervorst FBL, Manders P, Ligtenberg MJL, van den Ouweland AMW, Peock S, Cook M, Platte R, Evans DG, Eeles R, Pichert G, Chu C, Eccles D, Davidson R, Douglas F, Godwin AK, Barjhoux L, Mazoyer S, Sobol H, Bourdon V, Eisinger F, Chompret A, Capoulade C, Bressac-de Paillerets B, Lenoir GM, Gauthier-Villars M, Houdayer C, Stoppa-Lyonnet D, Chenevix-Trench G, Easton DF

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2008

Volume: 82

Issue: 4

Pages: 937-948

Print publication date: 11/04/2008

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.ajhg.2008.02.008

DOI: 10.1016/j.ajhg.2008.02.008

PubMed id: 18355772


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Funding

Funder referenceFunder name
Cancer Research UK
10118Cancer Research UK
1U01 CA 86389NCI NIH HHS
5U01 CA113916NCI NIH HHS
CA122340NCI NIH HHS
M01 RR000043NCRR NIH HHS
M01 RR00043NCRR NIH HHS
P50 CA083638NCI NIH HHS
P50 CA116201NCI NIH HHS
P50-CA116201NCI NIH HHS
R01 CA074415NCI NIH HHS
R01 CA102776NCI NIH HHS
R01 CA122340NCI NIH HHS
N02CP11019NCI NIH HHS
N02-CP-11019-50NCI NIH HHS
N02CP65504NCI NIH HHS
RC4 CA153828NCI NIH HHS
P30 CA051008NCI NIH HHS
P30 CA51008-12NCI NIH HHS
P-50 CA 83638NCI NIH HHS
R01 CA083855NCI NIH HHS
R01-CA083855NCI NIH HHS
R01-CA102776NCI NIH HHS
R01-CA74415NCI NIH HHS
U01 CA069631NCI NIH HHS
U01 CA086389NCI NIH HHS
U01 CA086389-09NCI NIH HHS
U01 CA113916NCI NIH HHS
U01 CA69631NCI NIH HHS

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