title: Polyposis and early cancer in a patient with low penetrant mutations in MSH6 and APC: hereditary colorectal cancer as a polygenic trait.
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.
authors.affiliation: Department of Clinical Biochemistry, Aalborg Hospital, Aarhus University, Aalborg, Denmark. u00326@aas.nja.dk
authors.forename: Henrik
authors.initials: H
authors.lastname: Okkels
authors.forename: Lone
authors.initials: L
authors.lastname: Sunde
authors.forename: Karen
authors.initials: K
authors.lastname: Lindorff-Larsen
authors.forename: Ole
authors.initials: O
authors.lastname: Thorlacius-Ussing
authors.forename: Per
authors.initials: P
authors.lastname: Gandrup
authors.forename: Jan
authors.initials: J
authors.lastname: Lindebjerg
authors.forename: Peter
authors.initials: P
authors.lastname: Stubbeteglbjaerg
authors.forename: John R
authors.initials: JR
authors.lastname: Oestergaard
authors.forename: Finn Cilius
authors.initials: FC
authors.lastname: Nielsen
authors.forename: Henrik Bygum
authors.initials: HB
authors.lastname: Krarup
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000236:Adenoma / Q000235:genetics; D011125:Adenomatous Polyposis Coli / Q000235:genetics; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000293:Adolescent; D018389:Codon, Nonsense; D003110:Colonic Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D020412:Multifactorial Inheritance; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D012004:Rectal Neoplasms / Q000235:genetics*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein