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A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer

Abstract

We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 SNPs in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls. We identified four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer and confirmed this association in 1,776 affected individuals and 2,072 controls from three additional studies. Across the four studies, the association with all four SNPs was highly statistically significant (Ptrend for the most strongly associated SNP (rs1219648) = 1.1 × 10−10; population attributable risk = 16%). Four SNPs at other loci most strongly associated with breast cancer in the initial GWAS were not associated in the replication studies. Our summary results from the GWAS are available online in a form that should speed the identification of additional risk loci.

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Figure 1: Summary of GWAS results by chromosome.
Figure 2: Association analysis of SNPs across FGFR2.

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Acknowledgements

We thank B. Egan, L. Egan, H. Judge Ellis, H. Ranu and P. Soule for assistance, and we thank the participants in the Nurses' Health Studies. We thank P. Prorok (Division of Cancer Prevention, National Cancer Institute); the Screening Center investigators and staff of PLCO; T. Riley, C. Williams and staff (Information Management Services, Inc.); B. O'Brien and staff (Westat, Inc.) and B. Kopp, T. Sheehy and staff (SAIC-Frederick). We acknowledge the study participants for their contributions in making this study possible. We thank C. Lichtman for data management and the participants on the CPS-II. We thank M. Minichiello for providing the Margarita program and for discussions. We acknowledge D. Easton and colleagues for sharing prepublication results. The Nurses' Health Studies are supported by US NIH grants CA65725, CA87969, CA49449, CA67262, CA50385 and 5UO1CA098233. The ACS study is supported by UO1 CA098710. The PLCO study is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS.

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Correspondence to David J Hunter.

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Supplementary information

Supplementary Fig. 1

Distribution of the admixture vector of each NHS participant as determined by STRUCTURE. (PDF 41 kb)

Supplementary Fig. 2

Probability-probability plot of the uncorrected P values (blue dots) compared with the expected uniform distribution (green line), where magenta dots show the P values corrected for age in 5-year intervals, an indicator for recent hormone use, and three eigenvectors controlling for population stratification. (PDF 77 kb)

Supplementary Fig. 3

ARG analysis with 81 SNPs after 106 permutations. (PDF 55 kb)

Supplementary Table 1

Identification of protective and at-risk haplotypes for the FGFR2 susceptibility locus. (PDF 79 kb)

Supplementary Table 2

Evidence for association between the six most significant SNPs in the NHS genome-wide association scan, the three replication studies, and the pooled scan and replication data. (PDF 56 kb)

Supplementary Methods (PDF 20 kb)

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Hunter, D., Kraft, P., Jacobs, K. et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39, 870–874 (2007). https://doi.org/10.1038/ng2075

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