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.
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Acknowledgments
We thank the patients and their families for participating in the study. We are grateful to Susanne Raeder, Dietlinde Stienen, and Siegfried Uhlhaas for their excellent technical support.
Funding
This work was supported by the German Cancer Aid (Deutsche Krebshilfe e.V. Bonn, Grant number 108421); the Gerok-Stipendium of the University Hospital Bonn (Grant no. O-149.0098); the NIH Centers for Mendelian Genomics (5U54HG006504); the Federal Ministry of Education and Research (0316190A); and the Volkswagenstiftung (Lichtenberg Program to M.R.S.). These funding sources had no involvement in the study design; the collection, analysis, or interpretation of data; the writing of the report; or the decision to submit the manuscript for publication. The corresponding author had full access to all study data, and had final responsibility for the decision to submit the manuscript for publication.
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Spier, I., Kerick, M., Drichel, D. et al. Exome sequencing identifies potential novel candidate genes in patients with unexplained colorectal adenomatous polyposis. Familial Cancer 15, 281–288 (2016). https://doi.org/10.1007/s10689-016-9870-z
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DOI: https://doi.org/10.1007/s10689-016-9870-z