Polyposis and early cancer in a patient with low penetrant mutations in MSH6 and APC: hereditary colorectal cancer as a polygenic trait.
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.
Okkels
Henrik
H
Department of Clinical Biochemistry, Aalborg Hospital, Aarhus University, Aalborg, Denmark. u00326@aas.nja.dk
Sunde
Lone
L
Lindorff-Larsen
Karen
K
Thorlacius-Ussing
Ole
O
Gandrup
Per
P
Lindebjerg
Jan
J
Stubbeteglbjaerg
Peter
P
Oestergaard
John R
JR
Nielsen
Finn Cilius
FC
Krarup
Henrik Bygum
HB
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*
D025601:Adenomatous Polyposis Coli Protein; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein