title: Oligogenic combinations associated with breast cancer risk in women under 53 years of age.
abstract: 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.
authors.affiliation: Program in Arthritis and Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA. astonc@omrf.ouhsc.edu
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Aston
authors.forename: David A
authors.initials: DA
authors.lastname: Ralph
authors.forename: Dominique P
authors.initials: DP
authors.lastname: Lalo
authors.forename: Sharmila
authors.initials: S
authors.lastname: Manjeshwar
authors.forename: Bobby A
authors.initials: BA
authors.lastname: Gramling
authors.forename: Daniele C
authors.initials: DC
authors.lastname: DeFreese
authors.forename: Amy D
authors.initials: AD
authors.lastname: West
authors.forename: Dannielle E
authors.initials: DE
authors.lastname: Branam
authors.forename: Linda F
authors.initials: LF
authors.lastname: Thompson
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Craft
authors.forename: Debra S
authors.initials: DS
authors.lastname: Mitchell
authors.forename: Craig D
authors.initials: CD
authors.lastname: Shimasaki
authors.forename: John J
authors.initials: JJ
authors.lastname: Mulvihill
authors.forename: Eldon R
authors.initials: ER
authors.lastname: Jupe
mesh_terms: D000293:Adolescent; D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012306:Risk