title: Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer.
abstract: Colorectal cancer (CRC) displays a complex pattern of inheritance. It is postulated that much of the missing heritability of CRC is enshrined in high-impact rare alleles, which are mechanistically and clinically important. In this study, we assay the impact of rare germline mutations on CRC, analysing high-coverage exome sequencing data on 1,006 early-onset familial CRC cases and 1,609 healthy controls, with additional sequencing and array data on up to 5,552 cases and 6,792 controls. We identify highly penetrant rare mutations in 16% of familial CRC. Although the majority of these reside in known genes, we identify POT1, POLE2 and MRE11 as candidate CRC genes. We did not identify any coding low-frequency alleles (1-5%) with moderate effect. Our study clarifies the genetic architecture of CRC and probably discounts the existence of further major high-penetrance susceptibility genes, which individually account for >1% of the familial risk. Our results inform future study design and provide a resource for contextualizing the impact of new CRC genes.
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chubb
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Peter
authors.identifier: 0000-0002-8348-5829
authors.initials: P
authors.lastname: Broderick
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Dobbins
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Frampton
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Ben
authors.identifier: 0000-0003-1783-6296
authors.initials: B
authors.lastname: Kinnersley
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Penegar
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Amy
authors.initials: A
authors.lastname: Price
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Yussanne P
authors.initials: YP
authors.lastname: Ma
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Sherborne
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Palles
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK.
authors.forename: Maria N
authors.identifier: 0000-0002-2503-4253
authors.initials: MN
authors.lastname: Timofeeva
authors.affiliation: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: D Timothy
authors.identifier: 0000-0002-8752-8785
authors.initials: DT
authors.lastname: Bishop
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK.
authors.forename: Malcolm G
authors.initials: MG
authors.lastname: Dunlop
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.|Division of Pathology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D000483:Alleles; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D012307:Risk Factors; D006113:United Kingdom