title: Adenoma development in familial adenomatous polyposis and MUTYH-associated polyposis: somatic landscape and driver genes.
abstract: Familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) are inherited disorders associated with multiple colorectal adenomas that lead to a very high risk of colorectal cancer. The somatic mutations that drive adenoma development in these conditions have not been investigated comprehensively. In this study we performed analysis of paired colorectal adenoma and normal tissue DNA from individuals with FAP or MAP, sequencing 14 adenoma whole exomes (eight MAP, six FAP), 55 adenoma targeted exomes (33 MAP, 22 FAP) and germline DNA from each patient, and a further 63 adenomas by capillary sequencing (41 FAP, 22 MAP). With these data we examined the profile of mutated genes, the mutational signatures and the somatic mutation rates, observing significant diversity in the constellations of mutated driver genes in different adenomas, and loss-of-function mutations in WTX (9%; p < 9.99e-06), a gene implicated in regulation of the WNT pathway and p53 acetylation. These data extend our understanding of the early events in colorectal tumourigenesis in the polyposis syndromes.
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Mamunur
authors.initials: M
authors.lastname: Rashid
authors.affiliation: Population Genomics of Adaptation, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Andrej
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Cathy H
authors.initials: CH
authors.lastname: Wilson
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Jessamy
authors.initials: J
authors.lastname: Tiffen
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Alistair G
authors.initials: AG
authors.lastname: Rust
authors.affiliation: The Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Stevens
authors.affiliation: Institute of Medical Genetics, Cardiff University School of Medicine, UK.|Institute of Cancer and Genetics, Cardiff University School of Medicine, UK.
authors.forename: Shelley
authors.initials: S
authors.lastname: Idziaszczyk
authors.affiliation: Institute of Medical Genetics, Cardiff University School of Medicine, UK.|Institute of Cancer and Genetics, Cardiff University School of Medicine, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Maynard
authors.affiliation: Institute of Medical Genetics, Cardiff University School of Medicine, UK.|Institute of Cancer and Genetics, Cardiff University School of Medicine, UK.
authors.forename: Geraint T
authors.initials: GT
authors.lastname: Williams
authors.affiliation: Population Genomics of Adaptation, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Ville
authors.initials: V
authors.lastname: Mustonen
authors.affiliation: Institute of Medical Genetics, Cardiff University School of Medicine, UK.|Institute of Cancer and Genetics, Cardiff University School of Medicine, UK.
authors.forename: Julian R
authors.initials: JR
authors.lastname: Sampson
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000473:pathology*; D045647:DNA Glycosylases / Q000235:genetics; D004252:DNA Mutational Analysis; D006801:Humans; D044483:Intestinal Polyposis / Q000235:genetics* / Q000473:pathology*; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics; D059467:Transcriptome
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase
keywords: APC; MUTYH; WTX; adenoma development; colorectal neoplasms; driver genes; exome sequencing; somatic landscape