title: Predisposition gene identification in common cancers by exome sequencing: insights from familial breast cancer.
abstract: The genetic component of breast cancer predisposition remains largely unexplained. Candidate gene case-control resequencing has identified predisposition genes characterised by rare, protein truncating mutations that confer moderate risks of disease. In theory, exome sequencing should yield additional genes of this class. Here, we explore the feasibility and design considerations of this approach. We performed exome sequencing in 50 individuals with familial breast cancer, applying frequency and protein function filters to identify variants most likely to be pathogenic. We identified 867,378 variants that passed the call quality filters of which 1,296 variants passed the frequency and protein truncation filters. The median number of validated, rare, protein truncating variants was 10 in individuals with, and without, mutations in known genes. The functional candidacy of mutated genes was similar in both groups. Without prior knowledge, the known genes would not have been recognisable as breast cancer predisposition genes. Everyone carries multiple rare mutations that are plausibly related to disease. Exome sequencing in common conditions will therefore require intelligent sample and variant prioritisation strategies in large case-control studies to deliver robust genetic evidence of disease association.
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK.
authors.forename: Katie
authors.initials: K
authors.lastname: Snape
authors.forename: Elise
authors.initials: E
authors.lastname: Ruark
authors.forename: Patrick
authors.initials: P
authors.lastname: Tarpey
authors.forename: Anthony
authors.initials: A
authors.lastname: Renwick
authors.forename: Clare
authors.initials: C
authors.lastname: Turnbull
authors.forename: Sheila
authors.initials: S
authors.lastname: Seal
authors.forename: Anne
authors.initials: A
authors.lastname: Murray
authors.forename: Sandra
authors.initials: S
authors.lastname: Hanks
authors.forename: Jenny
authors.initials: J
authors.lastname: Douglas
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: Nazneen
authors.initials: N
authors.lastname: Rahman
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D005796:Genes; D020022:Genetic Predisposition to Disease; D006801:Humans
chemical_list: D018389:Codon, Nonsense