|Title||Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases.|
|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Spier, I, Drichel, D, Kerick, M, Kirfel, J, Horpaopan, S, Laner, A, Holzapfel, S, Peters, S, Adam, R, Zhao, B, Becker, T, Lifton, RP, Perner, S, Hoffmann, P, Kristiansen, G, Timmermann, B, Nöthen, MM, Holinski-Feder, E, Schweiger, MR, Aretz, S|
|Journal||J Med Genet|
|Date Published||2016 Mar|
|Keywords||Adenomatous Polyposis Coli, Adolescent, Adult, Colorectal Neoplasms, Genes, APC, High-Throughput Nucleotide Sequencing, Humans, Middle Aged, Mutation, Mutation Rate|
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-proofreading-associated 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 low-level 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.
|Alternate Journal||J. Med. Genet.|
|Grant List||5U54HG006504 / HG / NHGRI NIH HHS / United States|