title: Breast cancer susceptibility loci in association with age at menarche, age at natural menopause and the reproductive lifespan.
abstract: BACKGROUND
  Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with breast cancer risk. Some of these loci have unknown functional significance and may mediate the effects of hormonal exposures on breast cancer risk. We examined relationships between breast cancer susceptibility variants and menstrual/reproductive factors using data from two population-based studies.
  
  
  METHODS
  The first analysis was based on a sample of 1328 women age 20-74 who participated as controls in a case-control study of breast cancer conducted in three U.S. states. We evaluated the associations between age at menarche, age at natural menopause and the reproductive lifespan with 13 previously identified breast cancer variants. Associations were also examined with a genetic score created as the sum of at-risk alleles across the 13 variants. For validation, significant results were evaluated in a second dataset comprised 1353 women age 43-86 recruited as part of a cohort study in Wisconsin.
  
  
  RESULTS
  Neither the genetic score nor any of the 13 variants considered individually were associated with age at menarche or reproductive lifespan. Two SNPs were associated with age at natural menopause; every increase in the minor allele (A) of rs17468277 (CASP8) was associated with a 1.12 year decrease in menopause age (p=0.02). The minor allele (G) of rs10941679 (5p12) was associated with a 1.01 year increase in age at natural menopause (p=0.01). The results were not replicated in the validation cohort (B=-0.61, p=0.14 and B=-0.01, p=.0.98, respectively).
  
  
  CONCLUSIONS
  The evaluated variants and reproductive experiences may work through separate pathways to influence breast cancer risk.
authors.affiliation: University of Wisconsin, Carbone Cancer Center, Madison, WI 53726, USA; Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA. Electronic address: snandersen@uwalumni.com.
authors.forename: Shaneda
authors.initials: S
authors.lastname: Warren Andersen
authors.affiliation: University of Wisconsin, Carbone Cancer Center, Madison, WI 53726, USA; Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Trentham-Dietz
authors.affiliation: Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Gangnon
authors.affiliation: University of Wisconsin, Carbone Cancer Center, Madison, WI 53726, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Hampton
authors.affiliation: Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA.
authors.forename: Halcyon G
authors.initials: HG
authors.lastname: Skinner
authors.affiliation: Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA.
authors.forename: Corinne D
authors.initials: CD
authors.lastname: Engelman
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Klein
authors.affiliation: Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03756, USA.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Titus
authors.affiliation: Division of Cancer Prevention and Control, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Egan
authors.affiliation: University of Wisconsin, Carbone Cancer Center, Madison, WI 53726, USA; Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008572:Menarche / Q000502:physiology; D008593:Menopause / Q000502:physiology; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017584:Reproductive History; D012307:Risk Factors; D014481:United States / Q000453:epidemiology; D055815:Young Adult
keywords: Breast cancer; Breast cancer susceptibility loci; Epidemiology; Menstrual factors