Abstract

Familial clustering studies indicate that breast cancer risk has a substantial genetic component1,2,3. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then tested selected SNPs in five replication sample sets. Overall, we studied 4,554 affected individuals and 17,577 controls. Two SNPs consistently associated with breast cancer: 25% of individuals of European descent are homozygous for allele A of rs13387042 on chromosome 2q35 and have an estimated 1.44-fold greater risk than noncarriers, and for allele T of rs3803662 on 16q12, about 7% are homozygous and have a 1.64-fold greater risk. Risk from both alleles was confined to estrogen receptor–positive tumors. At present, no genes have been identified in the linkage disequilibrium block containing rs13387042. rs3803662 is near the 5′ end of TNRC9 , a high mobility group chromatin–associated protein whose expression is implicated in breast cancer metastasis to bone4.

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Acknowledgements

We thank all participants for taking part in this research. We thank S. Sveinsdottir and K. Alexiusdottir for assistance in recruitment of patients and collection of clinical information. This project was funded in part by contract number 018827 (POLYGENE) from the 6th Framework Program of the European Union, the Swedish Cancer Society, the Gustav V Jubilee Foundation, the Bert von Kantzow Foundation and the Nilsson-Ehle Foundation.

Author information

Affiliations

  1. deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.

    • Simon N Stacey
    • , Andrei Manolescu
    • , Patrick Sulem
    • , Thorunn Rafnar
    • , Julius Gudmundsson
    • , Sigurjon A Gudjonsson
    • , Gisli Masson
    • , Margret Jakobsdottir
    • , Steinunn Thorlacius
    • , Agnar Helgason
    • , Magali Mouy
    • , Jona Saemundsdottir
    • , Valgerdur M Backman
    • , Larus Gudmundsson
    • , Kristleifur Kristjansson
    • , Jon T Bergthorsson
    • , Jelena Kostic
    • , Michael L Frigge
    • , Frank Geller
    • , Daniel Gudbjartsson
    • , Jeffrey R Gulcher
    • , Unnur Thorsteinsdottir
    • , Augustine Kong
    •  & Kari Stefansson
  2. Comprehensive Cancer Center IKO, 6501 BG, Nijmegen, The Netherlands.

    • Katja K Aben
  3. Departments of Epidemiology and Biostatistics and Clinical Chemistry, Radboud University Nijmegen Medical Center, 6500 HB, Nijmegen, The Netherlands.

    • Katja K Aben
    • , Dorine W Swinkels
    •  & Lambertus A Kiemeney
  4. Department of Surgery, Canisius Wilhelmina Hospital, 6500 GS Nijmegen, The Netherlands.

    • Luc J Strobbe
  5. INR Thrombosis Service, 6525 GA Nijmegen, The Netherlands.

    • Marjo T Albers-Akkers
  6. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.

    • Brian E Henderson
    •  & Christopher A Haiman
  7. Cancer Research Center, University of Hawaii, Honolulu, Hawaii 96813, USA.

    • Laurence N Kolonel
    •  & Loic Le Marchand
  8. Division of Medical Oncology, University Hospital, Av. San Juan Bosco 15, 50009 Zaragoza, Spain.

    • Esther Millastre
    • , Raquel Andres
    • , Alejandro Tres
    •  & Jose I Mayordomo
  9. Health Science Institute, Nanotechnology Institute of Aragon, Zaragoza, Spain.

    • Javier Godino
  10. Division of Pathology, San Jorge General Hospital, Av. Martínez de Velasco 38, 22004 Huesca, Spain.

    • Maria Dolores Garcia-Prats
  11. Division of Medical Oncology, Ernest Lluch Hospital, 50300 Calatayud, Spain.

    • Eduardo Polo
  12. Departments of Oncology, Surgery and Radiation Physics, Landspitali-University Hospital, 101 Reykjavik, Iceland.

    • Helgi Sigurdsson
    • , Thora Jonsdottir
    • , Jon Hrafnkelsson
    • , Jakob Johannsson
    • , Thorarinn Sveinsson
    • , Gardar Myrdal
    • , Hlynur Niels Grimsson
    • , Thorvaldur Jonsson
    •  & Oskar Th Johannsson
  13. Department of Molecular Medicine, Karolinska Institute, S171 76 Stockholm, Sweden.

    • Susanna von Holst
    • , Barbro Werelius
    •  & Annika Lindblom
  14. Department of Oncology, Karolinska University Hospital at Södersjukhuset, S118 83 Stockholm, Sweden.

    • Sara Margolin

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Competing interests

Simon N Stacey, Andrei Manolescu, Patrick Sulem, Thorunn Rafnar, Julius Gudmundsson, Sigurjon A Gudjonsson, Gisli Masson, Margret Jakobsdottir, Steinunn Thorlacius, Agnar Helgason, Magali Mouy, Jona Saemundsdottir, Valgerdur M Backman, Larus Gudmundsson, Kristleifur Kristjansson, Jon T Bergthorsson, Jelena Kostic, Michael L Frigge, Frank Geller, Daniel Gudbjartsson, Jeffrey R Gulcher, Unnur Thorsteinsdottir, Augustine Kong and Kari Stefansson are employees and/or shareholders of deCODE genetics.

Corresponding authors

Correspondence to Simon N Stacey or Kari Stefansson.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Q-Q plot for 311,524 SNPs.

  2. 2.

    Supplementary Table 1

    Association results for SNPs that did not replicate significantly outside Iceland.

  3. 3.

    Supplementary Table 2

    Comparison of recently diagnosed and long-term survivor groups of Icelandic breast cancer patients.

  4. 4.

    Supplementary Table 3

    Swedish Familial and consecutively recruited breast cancer patient groups.

  5. 5.

    Supplementary Table 4

    Odds ratios for A-rs13387042 and T-rs3803662 in carriers and noncarriers of the Icelandic BRCA2 999del5 mutation.

  6. 6.

    Supplementary Table 5

    Primers used in Centaurus SNP and PCR assays.

  7. 7.

    Supplementary Methods

About this article

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DOI

https://doi.org/10.1038/ng2064

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