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Risk of contralateral breast cancer associated with common variants in BRCA1 and BRCA2: potential modifying effect of BRCA1/BRCA2 mutation carrier status

  • Epidemiology
  • Published:
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Abstract

Rare deleterious mutations in BRCA1 and BRCA2 are associated with an elevated risk of breast and ovarian cancer. Whether or not common variants in these genes are independently associated with risk of breast cancer remains unclear. In this study, we included 632 Caucasian women with asynchronous contralateral breast cancer (CBC, cases) and 1,221 women with unilateral breast cancer (UBC, controls) from the WECARE (Women’s Environment, Cancer and Radiation Epidemiology) Study. BRCA1 and BRCA2 deleterious mutation status was measured using denaturing high-performance liquid chromatography followed by direct sequencing, yielding including 88 BRCA1 and 60 BRCA2 deleterious mutation carriers. We also genotyped samples on the Illumina Omni1-Quad platform. We assessed the association between CBC risk and common (minor allele frequency (MAF) > 0.05) single-nucleotide polymorphisms (SNPs) in BRCA1 (n SNPs = 22) and BRCA2 (n SNPs = 30) and haplotypes using conditional logistic regression accounting for BRCA1/BRCA2 mutation status. We found no significant associations between any single-SNPs or haplotypes of BRCA1 or BRCA2 and risk of CBC among all women. When we stratified by BRCA1 and BRCA2 mutation carrier status, we found suggestive evidence that risk estimates for selected SNPs in BRCA1 (rs8176318, rs1060915, and rs16940) and BRCA2 (rs11571686, rs206115, and rs206117) may differ in non-carriers and carriers of deleterious mutations in BRCA1 and BRCA2. One common haplotype on BRCA1 was inversely significantly associated with risk only among non-BRCA1 and BRCA2 carriers. The association between common variants in BRCA1 and BRCA2 and risk of CBC may differ depending on BRCA1 and BRCA2 mutation carrier status.

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Abbreviations

BRCA1 :

Breast cancer susceptibility gene 1

BRCA2 :

Breast cancer susceptibility gene 2

CBC:

Contralateral breast cancer

CI:

Confidence interval

OR:

Odds ratio

SNP:

Single-nucleotide polymorphism

UBC:

Unilateral breast cancer

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Acknowledgments

We thank the women who participated in the WECARE Study.

Funding

This work was supported by National Cancer Institute (grant numbers: R01 CA097397, U01 CA083178, R01 CA129639).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Harlyne J Norris Cancer Research Tower, 1450 Biggy Street Room 1509J, Los Angeles, CA, 90033, USA

    Jane C. Figueiredo, David V. Conti, Won D. Lee & Robert W. Haile

  2. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 307 East 63rd Street, 3rd Floor, New York, NY, 10065, USA

    Jennifer D. Brooks, Marinela Capanu & Jonine L. Bernstein

  3. Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Mayo Mail Code 715, 1-117 Moos, 20 Delaware Street, Minneapolis, MN, 55455, USA

    Jenny N. Poynter

  4. Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, P.O. Box 800733, Charlottesville, VA, 22908-0733, USA

    Sharon N. Teraoka & Patrick Concannon

  5. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, P.O. Box 19024, M4-C308, Seattle, WA, USA

    Kathleen E. Malone

  6. Division of Cancer Etiology, Department of Population Sciences, City of Hope Comprehensive Cancer Center, National Medical Center, 1500 East Duarte Road, Bldg 173, Duarte, CA, 91010, USA

    Leslie Bernstein

  7. Genetic Basis of Human Disease Division, Translational Genomic Research Institute, 445 N. Fifth Street, Phoenix, AZ, 85004, USA

    David J. Duggan & Ashley Siniard

  8. Department of Epidemiology, University of Iowa, C21-L GH, Iowa, IA, 52242, USA

    Charles F. Lynch

  9. Institute of Cancer Epidemiology, Danish Cancer Society, Strandboulevarden 49, 2100, Copenhagen, Denmark

    Jørgen H. Olsen

Authors
  1. Jane C. Figueiredo
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  2. Jennifer D. Brooks
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  3. David V. Conti
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  4. Jenny N. Poynter
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  5. Sharon N. Teraoka
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  6. Kathleen E. Malone
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  7. Leslie Bernstein
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  8. Won D. Lee
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  9. David J. Duggan
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  10. Ashley Siniard
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  11. Patrick Concannon
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  12. Marinela Capanu
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  13. Charles F. Lynch
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  14. Jørgen H. Olsen
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  15. Robert W. Haile
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  16. Jonine L. Bernstein
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Corresponding author

Correspondence to Jane C. Figueiredo.

Appendix: WECARE Study Collaborative Group

Appendix: WECARE Study Collaborative Group

Memorial Sloan Kettering Cancer Center (New York, NY): Jonine L. Bernstein, Ph.D. (WECARE Study P.I.), Colin B. Begg, Ph.D., Marinela Capanu, Ph.D., Xiaolin Liang, M.D., Anne S. Reiner, M.P.H., Tracy M. Layne, M.P.H.

City of Hope (Duarte, CA) (some work performed at University of Southern California, Los Angeles CA): Leslie Bernstein, Ph.D., Laura Donnelly-Allen.

Danish Cancer Society (Copenhagen, Denmark): Jørgen H. Olsen, M.D., D.M.Sc., Michael Andersson, M.D., D.M.Sc., Lisbeth Bertelsen, M.D. Ph.D., Per Guldberg, Ph.D., Lene Mellemkjær, Ph.D.

Fred Hutchinson Cancer Research Center (Seattle, WA): Kathleen E. Malone, Ph.D.

International Epidemiology Institute (Rockville, MD) and Vanderbilt University (Nashville, TN): John D. Boice Jr., Sc.D.

Lund University (Lund, Sweden): Åke Borg, Ph.D., Therese Törngren, M.Sc., Lina Tellhed, B.Sc.

National Cancer Institute (Bethesda, MD): Daniela Seminara, Ph.D. M.P.H.

New York University (New York, NY): Roy E. Shore, Ph.D., Dr. PH.

Norwegian Radium Hospital (Oslo, Norway): Laila Jansen, Anne-Lise Børresen-Dale, Ph.D. (also University of Oslo, Norway).

University of California at Irvine (Irvine, CA): Hoda Anton-Culver, Ph.D.

Joan Largent, Ph.D. M.P.H.

University of Iowa (Iowa City, IA): Charles F. Lynch, M.D., Ph.D., Jeanne DeWall, M.A.

University of Southern California (Los Angeles, CA): Robert W. Hailem Dr.PH., Graham Casey, Ph.D., Bryan Langholz, Ph.D., Duncan C. Thomas, Ph.D., Shanyan Xue, M.D., Nianmin Zhou, M.D., Anh T. Diep, Evgenia Ter-Karapetova.

University of Southern Maine (Portland, ME): W. Douglas Thompson, Ph.D.

University of Texas, M.D. Anderson Cancer Center (Houston, TX): Marilyn Stovall, Ph.D., Susan Smith, M.P.H.

University of Virginia (Charlottesville, VA) (some work performed at Benaroya Research Institute, Seattle WA): Patrick Concannon, Ph.D., Sharon N. Teraoka, Ph.D., Eric R. Olson, Ph.D., Nirasha Ramchurren, Ph.D.

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Figueiredo, J.C., Brooks, J.D., Conti, D.V. et al. Risk of contralateral breast cancer associated with common variants in BRCA1 and BRCA2: potential modifying effect of BRCA1/BRCA2 mutation carrier status. Breast Cancer Res Treat 127, 819–829 (2011). https://doi.org/10.1007/s10549-010-1285-1

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