title: Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles.
abstract: Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multi-generational breast cancer predisposition is unknown. In this study, we used whole-exome sequencing of thirty-three individuals from 15 breast cancer families to identify potential predisposing genes. Our analysis identified families with heterozygous, deleterious mutations in the DNA repair genes FANCC and BLM, which are responsible for the autosomal recessive disorders Fanconi Anemia and Bloom syndrome. In total, screening of all exons in these genes in 438 breast cancer families identified three with truncating mutations in FANCC and two with truncating mutations in BLM. Additional screening of FANCC mutation hotspot exons identified one pathogenic mutation among an additional 957 breast cancer families. Importantly, none of the deleterious mutations were identified among 464 healthy controls and are not reported in the 1,000 Genomes data. Given the rarity of Fanconi Anemia and Bloom syndrome disorders among Caucasian populations, the finding of multiple deleterious mutations in these critical DNA repair genes among high-risk breast cancer families is intriguing and suggestive of a predisposing role. Our data demonstrate the utility of intra-family exome-sequencing approaches to uncover cancer predisposition genes, but highlight the major challenge of definitively validating candidates where the incidence of sporadic disease is high, germline mutations are not fully penetrant, and individual predisposition genes may only account for a tiny proportion of breast cancer families.
authors.affiliation: Victorian Breast Cancer Research Consortium Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Ella R
authors.initials: ER
authors.lastname: Thompson
authors.forename: Maria A
authors.initials: MA
authors.lastname: Doyle
authors.forename: Georgina L
authors.initials: GL
authors.lastname: Ryland
authors.forename: Simone M
authors.initials: SM
authors.lastname: Rowley
authors.forename: David Y H
authors.initials: DY
authors.lastname: Choong
authors.forename: Richard W
authors.initials: RW
authors.lastname: Tothill
authors.forename: Heather
authors.initials: H
authors.lastname: Thorne
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Barnes
authors.forename: Jason
authors.initials: J
authors.lastname: Li
authors.forename: Jason
authors.initials: J
authors.lastname: Ellul
authors.forename: Gayle K
authors.initials: GK
authors.lastname: Philip
authors.forename: Yoland C
authors.initials: YC
authors.lastname: Antill
authors.forename: Paul A
authors.initials: PA
authors.lastname: James
authors.forename: Alison H
authors.initials: AH
authors.lastname: Trainer
authors.forename: Gillian
authors.initials: G
authors.lastname: Mitchell
authors.forename: Ian G
authors.initials: IG
authors.lastname: Campbell
mesh_terms: D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005091:Exons; D052218:Fanconi Anemia Complementation Group C Protein / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D010375:Pedigree; D011110:Polymorphism, Genetic; D053484:RecQ Helicases / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: C497651:FANCC protein, human; D052218:Fanconi Anemia Complementation Group C Protein; C097151:Bloom syndrome protein; D053484:RecQ Helicases