Human Genetics

, Volume 116, Issue 3, pp 208–221 | Cite as

Oligogenic combinations associated with breast cancer risk in women under 53 years of age

  • Christopher E. AstonEmail author
  • David A. Ralph
  • Dominique P. Lalo
  • Sharmila Manjeshwar
  • Bobby A. Gramling
  • Daniele C. DeFreese
  • Amy D. West
  • Dannielle E. Branam
  • Linda F. Thompson
  • Melissa A. Craft
  • Debra S. Mitchell
  • Craig D. Shimasaki
  • John J. Mulvihill
  • Eldon R. Jupe
Original Investigation


Common, but weakly penetrant, functional polymorphisms probably account for most of the genetic risk for breast cancer in the general population. Current polygenic risk models assume that component genes act independently. To test for potential gene–gene interactions, single nucleotide polymorphisms in ten genes with known or predicted roles in breast carcinogenesis were examined in a case-control study of 631 Caucasian women diagnosed with breast cancer under the age of 53 years and 1,504 controls under the age of 53 years. Association of breast cancer risk with individual genes and with two- and three-gene combinations was analyzed. Sixty-nine oligogenotypes from 37 distinct two- and three-gene combinations met stringent criteria for significance. Significant odds ratios (ORs) covered a 12-fold range: 0.5–5.9. Of the observed ORs, 17% differed significantly from the ORs predicted by a model of independent gene action, suggesting epistasis, i.e., that these genes interact to affect breast cancer risk in a manner not predictable from single gene effects. Exploration of the biological basis for these oligogenic interactions might reveal etiologic or therapeutic insights into breast cancer and other cancers.


Breast Cancer Breast Cancer Risk Benign Breast Disease Sporadic Breast Cancer Steroid Hormone Metabolism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by funding from the US Army Breast Cancer Research Program (E.R.J.), the American Cancer Society (E.R.J.), Oklahoma Center for the Advancement of Science and Technology (E.R.J. and D.A.R.), the University of Oklahoma Health Sciences Center General Clinical Research Center, the National Center for Research Resources—NIH, The Presbyterian Health Foundation, The Oklahoma Life Sciences Fund, and the Swisher Family Trust. We thank A. Whelan, A. Lee, and B. Howry for technical assistance, M. Bondy for critical comments, and the many clinicians and women who participated. The Molecular Biology Resource Facility at the University of Oklahoma Health Sciences Center provided oligonucleotide synthesis services. L.F.T. holds the Putnam City Schools Chair in Cancer Research. J.J.M. holds the Kimberly V. Talley/Children’s Medical Research Institute Chair in Genetics.


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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Christopher E. Aston
    • 1
    • 3
    • 4
    Email author
  • David A. Ralph
    • 3
  • Dominique P. Lalo
    • 3
  • Sharmila Manjeshwar
    • 2
    • 3
  • Bobby A. Gramling
    • 3
  • Daniele C. DeFreese
    • 3
  • Amy D. West
    • 3
  • Dannielle E. Branam
    • 2
  • Linda F. Thompson
    • 2
  • Melissa A. Craft
    • 7
  • Debra S. Mitchell
    • 7
  • Craig D. Shimasaki
    • 3
  • John J. Mulvihill
    • 4
  • Eldon R. Jupe
    • 2
    • 3
    • 5
    • 6
  1. 1.Program in Arthritis and ImmunologyOklahoma Medical Research FoundationOklahoma CityUSA
  2. 2.Program in Immunobiology and CancerOklahoma Medical Research FoundationOklahoma CityUSA
  3. 3.InterGeneticsOklahoma CityUSA
  4. 4.Department of PediatricsUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  5. 5.Department of SurgeryUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  6. 6.Department of PathologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  7. 7.Breast Imaging of OklahomaEdmondUSA

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