Adenoma development in familial adenomatous polyposis and MUTYH-associated polyposis: somatic landscape and driver genes

J Pathol. 2016 Jan;238(1):98-108. doi: 10.1002/path.4643. Epub 2015 Nov 2.


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.

Keywords: APC; MUTYH; WTX; adenoma development; colorectal neoplasms; driver genes; exome sequencing; somatic landscape.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli / genetics*
  • Adenomatous Polyposis Coli / pathology*
  • DNA Glycosylases / genetics
  • DNA Mutational Analysis
  • Humans
  • Intestinal Polyposis / genetics*
  • Intestinal Polyposis / pathology*
  • Neoplastic Syndromes, Hereditary / genetics
  • Transcriptome


  • DNA Glycosylases
  • mutY adenine glycosylase