title: Breast cancer susceptibility variants alter risks in familial disease.
abstract: BACKGROUND
  Recent candidate and genome-wide association studies have identified variants altering susceptibility to breast cancer.
  
  
  OBJECTIVE
  To establish the relevance of these variants to breast cancer risk in familial breast cancer cases both with and without BRCA1 or BRCA2 (BRCA1/2) mutations.
  
  
  METHODS
  A cohort of unrelated individuals with breast cancer due to the presence of either BRCA1 (121) or BRCA2 mutations (109) and individuals with familial breast cancer not due to BRCA1/2 mutations (722) were genotyped using Taqman SNP Genotyping Assays. Allele frequencies were compared with an ethnically and gender-matched group (436).
  
  
  RESULTS
  A synonymous variant (Ser51) in TOX3 (previously TNRC9) was associated with an increased risk of breast cancer (OR=1.82, p<0.001) in BRCA2 mutation carriers. The associations for FGFR2 (OR=1.20, p=0.046), TOX3 (OR=1.5, p<0.001), MAP3K1 (OR=1.26 p=0.03), CASP8 (OR=0.73 p=0.02) and the chromosome 8-associated SNP (OR=1.31, p=0.004) were replicated in individuals without BRCA1/2 mutations. In addition, homozygote carriers of MAP3K1 variants were shown to have a significantly lower Manchester Score (mean 13.8-17.6, p=0.003), whereas individuals carrying one or two copies of the FGFR2 variant had a higher Manchester Score (mean 17.5-17.9, p=0.01).
  
  
  CONCLUSIONS
  This study confirms that susceptibility variants in FGFR2, TOX3 and MAP3K1 and on chromosome 8q are all associated with increased risk of cancer in individuals with a family history of breast cancer, whereas CASP8 is protective in this context. The level of risk is dependent on the strength of the family history and the presence of a BRCA1/2 mutation and contributes to the understanding of the use of these variants in clinical risk prediction.
authors.affiliation: Department of Medical Genetics, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester M13 0JH, UK.
authors.forename: Ayse
authors.initials: A
authors.lastname: Latif
authors.forename: Kristen D
authors.initials: KD
authors.lastname: Hadfield
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Roberts
authors.forename: Andrew
authors.initials: A
authors.lastname: Shenton
authors.forename: Fiona
authors.initials: F
authors.lastname: Lalloo
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Black
authors.forename: Anthony
authors.initials: A
authors.lastname: Howell
authors.forename: D Gareth
authors.initials: DG
authors.lastname: Evans
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics*; D053181:Caspase 8 / Q000235:genetics; D016009:Chi-Square Distribution; D015331:Cohort Studies; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D018570:Risk Assessment
chemical_list: C489183:LSP1 protein, human; D008840:Microfilament Proteins; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; C505530:CASP8 protein, human; D053181:Caspase 8