title: Validation of Recently Proposed Colorectal Cancer Susceptibility Gene Variants in an Analysis of Families and Patients-a Systematic Review.
abstract: High-throughput sequencing analysis has accelerated searches for genes associated with risk for colorectal cancer (CRC); germline mutations in NTHL1, RPS20, FANCM, FAN1, TP53, BUB1, BUB3, LRP6, and PTPN12 have been recently proposed to increase CRC risk. We attempted to validate the association between variants in these genes and development of CRC in a systematic review of 11 publications, using sequence data from 863 familial CRC cases and 1604 individuals without CRC (controls). All cases were diagnosed at an age of 55 years or younger and did not carry mutations in an established CRC predisposition gene. We found sufficient evidence for NTHL1 to be considered a CRC predisposition gene-members of 3 unrelated Dutch families were homozygous for inactivating p.Gln90Ter mutations; a Canadian woman with polyposis, CRC, and multiple tumors was reported to be heterozygous for the inactivating NTHL1 p.Gln90Ter/c.709+1G>A mutations; and a man with polyposis was reported to carry p.Gln90Ter/p.Gln287Ter; whereas no inactivating homozygous or compound heterozygous mutations were detected in controls. Variants that disrupted RPS20 were detected in a Finnish family with early-onset CRC (p.Val50SerfsTer23), a 39-year old individual with metachronous CRC (p.Leu61GlufsTer11 mutation), and a 41-year-old individual with CRC (missense p.Val54Leu), but not in controls. We therefore found published evidence to support the association between variants in NTHL1 and RPS20 with CRC, but not of other recently reported CRC susceptibility variants. We urge the research community to adopt rigorous statistical and biological approaches coupled with independent replication before making claims of pathogenicity.
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Broderick
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Dobbins
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chubb
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Kinnersley
authors.affiliation: Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh.
authors.forename: Malcolm G
authors.initials: MG
authors.lastname: Dunlop
authors.affiliation: Molecular and Population Genetics Laboratory and NIHR Biomedical Research Centre, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Division of Pathology, The Institute of Cancer Research, London, UK. Electronic address: richard.houlston@icr.ac.uk.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D043224:Deoxyribonuclease (Pyrimidine Dimer) / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D012269:Ribosomal Proteins / Q000235:genetics*
chemical_list: D012269:Ribosomal Proteins; C029611:ribosomal protein S20; D043224:Deoxyribonuclease (Pyrimidine Dimer); C468347:NTHL1 protein, human
keywords: Colon Cancer; Exome Sequencing; Germline; Inherited