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Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles

Thompson, Ella R ; Doyle, Maria A ; Ryland, Georgina L ; Rowley, Simone M ; Choong, David Y H ; Tothill, Richard W ; Thorne, Heather ; Barnes, Daniel R ; Li, Jason ; Ellul, Jason ; Philip, Gayle K ; Antill, Yoland C ; James, Paul A ; Trainer, Alison H ; Mitchell, Gillian ; Campbell, Ian G Horwitz, Marshall S.

PLoS genetics, 2012-09, Vol.8 (9), p.e1002894 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles
Autor: Thompson, Ella R ; Doyle, Maria A ; Ryland, Georgina L ; Rowley, Simone M ; Choong, David Y H ; Tothill, Richard W ; Thorne, Heather ; Barnes, Daniel R ; Li, Jason ; Ellul, Jason ; Philip, Gayle K ; Antill, Yoland C ; James, Paul A ; Trainer, Alison H ; Mitchell, Gillian ; Campbell, Ian G
Horwitz, Marshall S.
Assuntos: Alleles ; Allelomorphism ; Biology ; Breast cancer ; Breast Neoplasms - genetics ; Cancer ; Development and progression ; Disease susceptibility ; DNA repair ; DNA sequencing ; Exome - genetics ; Exons ; Family medical history ; Fanconi Anemia Complementation Group C Protein - genetics ; Fanconi Anemia Complementation Group C Protein - metabolism ; Female ; Genes ; Genetic aspects ; Genetic Predisposition to Disease ; Genome, Human ; Health aspects ; Humans ; Medical research ; Mutation ; Nucleotide sequencing ; Pedigree ; Physiological aspects ; Polymorphism, Genetic ; RecQ Helicases - genetics ; RecQ Helicases - metabolism ; Sequence Analysis, DNA ; Sequence Deletion - genetics
É parte de: PLoS genetics, 2012-09, Vol.8 (9), p.e1002894
Notas: Conceived and designed the experiments: IGC GM ERT. Performed the experiments: ERT GLR RWT SMR DYHC YCA. Analyzed the data: ERT MAD JL JE GKP DRB. Contributed reagents/materials/analysis tools: kConFab HT GM PAJ AHT. Wrote the paper: ERT IGC AHT.
The authors have declared that no competing interests exist.
Descrição: 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.
Editor: United States: Public Library of Science
Idioma: Inglês

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Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles

United States: Public Library of Science

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