title: A family-based, genome-wide association study of young-onset breast cancer: inherited variants and maternally mediated effects.
abstract: Young-onset breast cancer shows certain phenotypic and etiologic differences from older-onset breast cancer and may be influenced by some distinct genetic variants. Few genetic studies of breast cancer have targeted young women and no studies have examined whether maternal variants influence disease in their adult daughters through prenatal effects. We conducted a family-based, genome-wide association study of young-onset breast cancer (age at diagnosis <50 years). A total of 602 188 single-nucleotide polymorphisms (SNPs) were genotyped for 1279 non-Hispanic white cases and their parents or sisters. We used likelihood-based log-linear models to test for transmission asymmetry within families and for maternally mediated genetic effects. Three autosomal SNPs (rs28373882, P=2.8 × 10(-7); rs879162, P=9.2 × 10(-7); rs12606061, P=9.1 × 10(-7)) were associated with risk of young-onset breast cancer at a false-discovery rate below 0.20. None of these loci has been previously linked with young-onset or overall breast cancer risk, and their functional roles are unknown. There was no evidence of maternally mediated, X-linked, or mitochondrial genetic effects, and no notable findings within cancer subcategories defined by menopausal status, estrogen receptor status, or by tumor invasiveness. Further investigations are needed to explore other potential genetic, epigenetic, or epistatic mechanisms and to confirm the association between these three novel loci and young-onset breast cancer.
authors.affiliation: Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Katie M
authors.initials: KM
authors.lastname: O'Brien
authors.affiliation: Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Shi
authors.affiliation: Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Dale P
authors.initials: DP
authors.lastname: Sandler
authors.affiliation: Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Taylor
authors.affiliation: Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Zaykin
authors.affiliation: Westat Inc., Durham, NC, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Keller
authors.affiliation: Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Alison S
authors.initials: AS
authors.lastname: Wise
authors.affiliation: Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Clarice R
authors.initials: CR
authors.lastname: Weinberg
mesh_terms: D000328:Adult; D017668:Age of Onset; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D018392:Genomic Imprinting; D006801:Humans; D008297:Male; D008875:Middle Aged; D009035:Mothers; D000072740:Paternal Inheritance; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D035781:Siblings