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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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.

Author information

Affiliations

  1. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

    • David J Hunter
    • , David G Cox
    • , Susan E Hankinson
    •  & Walter C Willett
  2. Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • David J Hunter
    • , Peter Kraft
    •  & David G Cox
  3. Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.

    • David J Hunter
  4. Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Bethesda, Maryland 20892, USA.

    • David J Hunter
    • , Meredith Yeager
    • , Sholom Wacholder
    • , Zhaoming Wang
    • , Robert Welch
    • , Amy Hutchinson
    • , Junwen Wang
    • , Kai Yu
    • , Nilanjan Chatterjee
    • , Regina G Ziegler
    • , Richard B Hayes
    • , Margaret Tucker
    • , Joseph F Fraumeni Jr
    • , Robert N Hoover
    • , Gilles Thomas
    •  & Stephen J Chanock
  5. Bioinformed Consulting Services, Gaithersburg, Maryland 20877, USA.

    • Kevin B Jacobs
  6. SAIC-Frederick, NCI-FCRDC, Frederick, Maryland 21702, USA.

    • Meredith Yeager
    • , Zhaoming Wang
    • , Robert Welch
    • , Amy Hutchinson
    •  & Junwen Wang
  7. Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, DHHS, Bethesda, Maryland 20892, USA.

    • Nick Orr
    •  & Stephen J Chanock
  8. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

    • Walter C Willett
  9. Washington University School of Medicine, St. Louis, Missouri 63130, USA.

    • Graham A Colditz
  10. Division of Cancer Prevention, NCI, NIH, DHHS, Bethesda, Maryland 20892, USA.

    • Christine D Berg
  11. Department of Internal Medicine, University of Utah, Salt Lake City, Utah 84112, USA.

    • Saundra S Buys
  12. The Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin 54449, USA.

    • Catherine A McCarty
  13. Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, Georgia 30329, USA.

    • Heather Spencer Feigelson
    • , Eugenia E Calle
    •  & Michael J Thun
  14. Office of Cancer Genomics, NCI, NIH, DHHS, Bethesda, Maryland 20892, USA.

    • Daniela S Gerhard

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Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Distribution of the admixture vector of each NHS participant as determined by STRUCTURE.

  2. 2.

    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.

  3. 3.

    Supplementary Fig. 3

    ARG analysis with 81 SNPs after 106 permutations.

  4. 4.

    Supplementary Table 1

    Identification of protective and at-risk haplotypes for the FGFR2 susceptibility locus.

  5. 5.

    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.

  6. 6.

    Supplementary Methods

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DOI

https://doi.org/10.1038/ng2075

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