Helmholtz Gemeinschaft


Exome sequencing identifies potential novel candidate genes in patients with unexplained colorectal adenomatous polyposis

Item Type:Article
Title:Exome sequencing identifies potential novel candidate genes in patients with unexplained colorectal adenomatous polyposis
Creators Name:Spier, I. and Kerick, M. and Drichel, D. and Horpaopan, S. and Altmüller, J. and Laner, A. and Holzapfel, S. and Peters, S. and Adam, R. and Zhao, B. and Becker, T. and Lifton, R.P. and Holinski-Feder, E. and Perner, S. and Thiele, H. and Nöthen, M.M. and Hoffmann, P. and Timmermann, B. and Schweiger, M.R. and Aretz, S.
Abstract:In up to 30 % of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, and POLE or POLD1, causing Polymerase-Proofreading-associated polyposis can be identified, although a hereditary etiology is likely. To uncover new causative genes, exome sequencing was performed using DNA from leukocytes and a total of 12 colorectal adenomas from seven unrelated patients with unexplained sporadic adenomatous polyposis. For data analysis and variant filtering, an established bioinformatics pipeline including in-house tools was applied. Variants were filtered for rare truncating point mutations and copy-number variants assuming a dominant, recessive, or tumor suppressor model of inheritance. Subsequently, targeted sequence analysis of the most promising candidate genes was performed in a validation cohort of 191 unrelated patients. All relevant variants were validated by Sanger sequencing. The analysis of exome sequencing data resulted in the identification of rare loss-of-function germline mutations in three promising candidate genes (DSC2, PIEZO1, ZSWIM7). In the validation cohort, further variants predicted to be pathogenic were identified in DSC2 and PIEZO1. According to the somatic mutation spectra, the adenomas in this patient cohort follow the classical pathways of colorectal tumorigenesis. The present study identified three candidate genes which might represent rare causes for a predisposition to colorectal adenoma formation. Especially PIEZO1 (FAM38A) and ZSWIM7 (SWS1) warrant further exploration. To evaluate the clinical relevance of these genes, investigation of larger patient cohorts and functional studies are required.
Keywords:Familial Colorectal Cancer, Adenomatous Polyposis, Candidate Genes, Exome Sequencing, Massive Parallel Sequencing, Hereditary Tumor Syndromes
Source:Familial Cancer
Page Range:281-288
Date:April 2016
Official Publication:https://doi.org/10.1007/s10689-016-9870-z
PubMed:View item in PubMed

Repository Staff Only: item control page

Open Access
MDC Library