Polyposis and early cancer in a patient with low penetrant mutations in MSH6 and APC: hereditary colorectal cancer as a polygenic trait

International Journal of Colorectal Disease
Henrik OkkelsHenrik Bygum Krarup

Abstract

Hereditary non-polyposis colorectal cancer and familial adenomatus polyposis are autosomal dominant diseases accounting for 5-7% of all colorectal cancer cases. Inheritance of mutations associated with both syndromes in the same individual has, so far, only been observed in a few cases. This report outlines the findings in a proband of a HNPCC family, who presented with colorectal cancer and with multiple adenomas at the age of 18. He was shown to be compound heterozygous for MSH6 mutations: a nonsense mutation in exon 4 (c.1836 C>A, p.S612X); and a missense mutation in exon 5 (c.3226 C>T, p.R1076C). In addition, an APC missense mutation was revealed (c.7504 G>A, p.G2502S). Immunohisto-chemical analysis showed lack of expression of MSH6 in tumour tissue, as well as accumulation of betacatenin in the nuclei of the tumour cells. We suggest that the presence of mutations in both alleles of one gene and mutations in different genes, may influence the phenotype in hereditary colorectal cancer. Biallelic and/or polygenic mutations should be suspected when facing unusual severe variants of "classic monogenic phenotypes", such as HNPCC.

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Citations

Apr 13, 2012·Applied Immunohistochemistry & Molecular Morphology : AIMM·Henrik OkkelsHenrik Bygum Krarup
May 9, 2008·Colorectal Disease : the Official Journal of the Association of Coloproctology of Great Britain and Ireland·J MartellucciG Tanzini
Aug 14, 2012·Familial Cancer·Noralane M LindorStephen N Thibodeau
Sep 14, 2015·Surgical Oncology Clinics of North America·Kory Jasperson, Randall W Burt
Jun 10, 2016·Cellular Oncology (Dordrecht)·M M HahnA Geurts van Kessel
Jun 10, 2010·The American Journal of Gastroenterology·Carol A DurnoSteven Gallinger
Jun 9, 2020·Frontiers in Genetics·Dustin B Miller, Stephen R Piccolo
Feb 6, 2021·Hereditary Cancer in Clinical Practice·Christa SlaughtSancy A Leachman

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