Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases

Isabel Spier*, Dmitriy Drichel, Martin Kerick, Jutta Kirfel, Sukanya Horpaopan, Andreas Laner, Stefanie Holzapfel, Sophia Peters, Ronja Adam, Bixiao Zhao, Tim Becker, Richard P. Lifton, Sven Perner, Per Hoffmann, Glen Kristiansen, Bernd Timmermann, Markus M. Nöthen, Elke Holinski-Feder, Michal R. Schweiger, Stefan Aretz

*Corresponding author for this work
33 Citations (Scopus)


Background In 30-50% of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, or POLE or POLD1, causing polymerase-proofreadingassociated polyposis can be identified, although a hereditary aetiology is likely. This study aimed to explore the impact of APC mutational mosaicism in unexplained polyposis. Methods To comprehensively screen for somatic lowlevel APC mosaicism, high-coverage next-generation sequencing of the APC gene was performed using DNA from leucocytes and a total of 53 colorectal tumours from 20 unrelated patients with unexplained sporadic adenomatous polyposis. APC mosaicism was assumed if the same loss-of-function APC mutation was present in ≥2 anatomically separated colorectal adenomas/carcinomas per patient. All mutations were validated using diverse methods. Results In 25% (5/20) of patients, somatic mosaicism of a pathogenic APC mutation was identified as underlying cause of the disease. In 2/5 cases, the mosaic level in leucocyte DNA was slightly below the sensitivity threshold of Sanger sequencing; while in 3/5 cases, the allelic fraction was either very low (0.1-1%) or no mutations were detectable. The majority of mosaic mutations were located outside the somatic mutation cluster region of the gene. Conclusions The present data indicate a high prevalence of pathogenic mosaic APC mutations below the detection thresholds of routine diagnostics in adenomatous polyposis, even if high-coverage sequencing of leucocyte DNA alone is taken into account. This has important implications for both routine work-up and strategies to identify new causative genes in this patient group.

Original languageEnglish
JournalJournal of Medical Genetics
Issue number3
Pages (from-to)172-179
Number of pages8
Publication statusPublished - 2016


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