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. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Burden and Profile of Somatic Mutation in Duodenal Adenomas from Patients with Familial Adenomatous- and MUTYH-associated Polyposis

“…A number of genes such as MLL3 and ATRNL1 in which we identified only single truncating mutations were also mutated recurrently in FAP and/or MAP colorectal adenomas in other recent studies (20). They represent candidate driver genes in duodenal as well as colorectal tumorigenesis.…”

“…We did not observe any somatic WTX mutations in 60 independent duodenal adenomas (Table 3). This was significantly different (P ¼ 0.0038, Fisher exact test) to the findings reported by Rashid and colleagues (20) in FAP and MAP colorectal adenomas, where 17 truncating mutations were identified in 128 adenomas, making WTX the most frequently mutated gene after APC. WTX forms a complex with APC, Axin, and b-TrCP2 that degrades b-catenin.…”

“…Recently, a comprehensive survey of the mutational landscape of colorectal adenomas from patients with FAP and MAP was made using exome sequencing (20). This confirmed the importance of somatic APC and KRAS mutations as drivers of early colorectal tumorigenesis in both disease settings.…”

“…Four of six mutations identified in this study were missense changes clustered around the X-Box region of the PLC core domain. A truncating mutation of PLCL1 (S931X) was also identified in 1 of 14 colorectal adenoma exomes in the study of Rashid and colleagues (20). PTCHD2 (DISP3) has been assigned to the family of Patcheddomain containing receptors based on in silico characterization and is likely involved in Hedgehog signaling (47).…”

“…35; P ¼ 0.004). Although whole exome sequencing did not identify any mutations in WTX, it was identified recently as a frequently mutated gene in FAP and MAP colorectal adenomas (20) and is also among the most frequently mutated genes in nonhypermutated colorectal cancer (21). We therefore also sequenced WTX in 42 further duodenal adenomas.…”