title: Interactions between genetic variants and breast cancer risk factors in the breast and prostate cancer cohort consortium.
abstract: BACKGROUND
  Recently, several genome-wide association studies have identified various genetic susceptibility loci for breast cancer. Relatively little is known about the possible interactions between these loci and the established risk factors for breast cancer.
  
  
  METHODS
  To assess interactions between single-nucleotide polymorphisms (SNPs) and established risk factors, we prospectively collected DNA samples and questionnaire data from 8576 breast cancer case subjects and 11 892 control subjects nested within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). We genotyped 17 germline SNPs (FGFR2-rs2981582, FGFR2-rs3750817, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, CASP8-rs1045485, LSP1-rs3817198, COL1A1-rs2075555, COX11-rs6504950, RNF146-rs2180341, 6q25-rs2046210, SLC4A7-rs4973768, NOTCH2-rs11249433, 5p12-rs4415084, 5p12-rs10941679, RAD51L1-rs999737), and odds ratios were estimated by logistic regression to confirm previously reported associations with breast cancer risk. We performed likelihood ratio test to assess interactions between 17 SNPs and nine established risk factors (age at menarche, parity, age at menopause, use of hormone replacement therapy, family history, height, body mass index, smoking status, and alcohol consumption), and a correction for multiple testing of 153 tests (adjusted P value threshold = .05/153 = 3 × 10(-4)) was done. Case-case comparisons were performed for possible differential associations of polymorphisms by subgroups of tumor stage, estrogen and progesterone receptor status, and age at diagnosis. All statistical tests were two-sided.
  
  
  RESULTS
  We confirmed the association of 14 SNPs with breast cancer risk (P(trend) = 2.57 × 10(-3) -3.96 × 10(-19)). Three SNPs (LSP1-rs3817198, COL1A1-rs2075555, and RNF146-rs2180341) did not show association with breast cancer risk. After accounting for multiple testing, no statistically significant interactions were detected between the 17 SNPs and the nine risk factors. We also confirmed that SNPs in FGFR2 and TNRC9 were associated with greater risk of estrogen receptor-positive than estrogen receptor-negative breast cancer (P(heterogeneity) = .0016 for FGFR2-rs2981582 and P(heterogeneity) = .0053 for TNRC9-rs3803662). SNP 5p12-rs10941679 was statistically significantly associated with greater risk of progesterone receptor-positive than progesterone receptor-negative breast cancer (P(heterogeneity) = .0028).
  
  
  CONCLUSIONS
  This study does not support the hypothesis that known common breast cancer susceptibility loci strongly modify the associations between established risk factors and breast cancer.
authors.affiliation: Genomic Epidemiology Group, German Cancer Research Center (Deutsches Krebsforschungszentrum; DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Daniele
authors.initials: D
authors.lastname: Campa
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kaaks
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Travis
authors.forename: Christine D
authors.initials: CD
authors.lastname: Berg
authors.forename: Julie E
authors.initials: JE
authors.lastname: Buring
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: W Ryan
authors.initials: WR
authors.lastname: Diver
authors.forename: Lucie
authors.initials: L
authors.lastname: Dostal
authors.forename: Agnes
authors.initials: A
authors.lastname: Fournier
authors.forename: Susan E
authors.initials: SE
authors.lastname: Hankinson
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.forename: Robert N
authors.initials: RN
authors.lastname: Hoover
authors.forename: Claudine
authors.initials: C
authors.lastname: Isaacs
authors.forename: Mattias
authors.initials: M
authors.lastname: Johansson
authors.forename: Laurence N
authors.initials: LN
authors.lastname: Kolonel
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: I-Min
authors.initials: IM
authors.lastname: Lee
authors.forename: Catherine A
authors.initials: CA
authors.lastname: McCarty
authors.forename: Kim
authors.initials: K
authors.lastname: Overvad
authors.forename: Salvatore
authors.initials: S
authors.lastname: Panico
authors.forename: Petra H M
authors.initials: PH
authors.lastname: Peeters
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Sanchez
authors.forename: Fredrick R
authors.initials: FR
authors.lastname: Schumacher
authors.forename: Guri
authors.initials: G
authors.lastname: Skeie
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Stram
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thun
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Trichopoulos
authors.forename: Shumin
authors.initials: S
authors.lastname: Zhang
authors.forename: Regina G
authors.initials: RG
authors.lastname: Ziegler
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Sara
authors.initials: S
authors.lastname: Lindström
authors.forename: Federico
authors.initials: F
authors.lastname: Canzian
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects; D015992:Body Mass Index; D001943:Breast Neoplasms / Q000737:chemistry / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D015986:Confounding Factors, Epidemiologic; D015914:Estrogen Replacement Therapy; D005060:Europe / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008593:Menopause; D009367:Neoplasm Staging; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D018570:Risk Assessment; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics
chemical_list: D011960:Receptors, Estrogen; D011980:Receptors, Progesterone