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

TitleExome sequencing identifies potential novel candidate genes in patients with unexplained colorectal adenomatous polyposis.
Publication TypeJournal Article
Year of Publication2016
AuthorsSpier, I, Kerick, M, Drichel, D, Horpaopan, S, Altmüller, J, Laner, A, Holzapfel, S, Peters, S, Adam, R, Zhao, B, Becker, T, Lifton, RP, Holinski-Feder, E, Perner, S, Thiele, H, Nöthen, MM, Hoffmann, P, Timmermann, B, Schweiger, MR, Aretz, S
JournalFam Cancer
Date Published2016 Apr
KeywordsAdenomatous Polyposis Coli, Adenomatous Polyps, Aged, Desmocollins, Exome, Female, Genetic Predisposition to Disease, Germ-Line Mutation, High-Throughput Nucleotide Sequencing, Humans, Ion Channels, Male, Middle Aged, Reproducibility of Results

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.

Alternate JournalFam. Cancer
PubMed ID26780541
Grant List5U54HG006504 / HG / NHGRI NIH HHS / United States