These results coupled with the tentative assignment of an HNPCC gene to chromosome 18 suggests that a gene on chromosome 18 may be involved in the etiology of some colon cancers.
Amongst the important known susceptibility genes are those dominant genes conferring a high risk of breast and ovarian cancer (BRCA1), colon cancer (hMSH2 and hMLH1), and melanoma (MLM).
We analyzed microsatellite instability, alterations of the polyadenine tract in TGF-beta RII (transforming growth factor beta type II receptor gene), and mutations of hMSH2 and hMLH1 in 32 patients with familial colorectal cancer (29 kindreds) fulfilling the clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC), defined at the 34th Annual Meeting of Japanese Society for Cancer of the Colon and Rectum (Tokushima, Japan, 1991), including five kindreds fulfilling the Amsterdam criteria.
Our results show that germline mutations of hMSH2 and hMLH1 genes contribute to a significant fraction of familial predisposition to colon cancer cases that do not fulfil all diagnostic criteria of HNPCC.
The human colon cancer cell line HCT116 is deficient in DNA mismatch repair (MMR) because of a genetic defect in the hMLH1 gene, which is located on chromosome 3.
Germ-line hMLH1 mutations are causally associated with inherited MSI colon cancer, and somatic mutations are causally associated with sporadic MSI colon cancer.
We focused on colon cancers from kindreds sharing one of two predisposing mutations (mutation 1 or 2) in the mismatch repair gene MLH1 (78 and 14 tumors, respectively).
We have studied the possible interactions between the mismatch repair system and p53 in a human colon cancer cell line, HCT-116 (known to have a homozygous mutation in mismatch repair gene hMLH1 on chromosome 3) and in a clone obtained after insertion of a single copy of chromosome 3 (HCT-116+ ch3).
We report the case of a 53-year-old man who had a history of colon cancers related to constitutional hMLH1 mutation and who was diagnosed as having a duodenal follicular lymphoma This diagnosis was supported by IgH-BCL2 rearrangement and BCL2 immunoreactivity in tumor cells.
We conclude that germ-line involvement of MSH6 and MSH3 is rare and that other genes are likely to account for a majority of MSH2-, MLH1-mutation negative families with nonpolypotic colon cancer.
Members of hereditary nonpolyposis colon cancer (HNPCC) families harboring heterozygous germline mutations in the DNA mismatch repair genes hMSH2 or hMLH1 present with tumors generally two to three decades earlier than individuals with nonfamilial sporadic colon cancer.
While a colon cancer from the same individual showed MSI, the BC specimen was MSI-negative, indicating that development of the latter tumor was unrelated to MMR impairment, despite presence of a constitutional MLH1 mutation.Hum Mutat 17:521, 2001.
Importantly, families with the MLH1 exon 16 mutation displayed significant variation (P = 0.012) in the age at onset of colon cancer, despite shared predisposition.
This type of genetic instability is a key event in the malignant progression of HNPCC and a subset of sporadic colon cancers and mutation rates are particularly high at short repetitive sequences.
To evaluate this possibility, we treated three colon cancer cell lines that are either proficient in mismatch repair (MMR) [SW480 (MMR wild type)] or deficient in MMR [HCT116 (hMLH1 mutant) and HCT15 (hMSH6 mutant)] with three cycles of BG+BCNU.
Three human colon cancer cell lines were used, SW480 cells, which are wild-type for mismatch repair genes and have mutated p53, HCT116 cells, which are mutant in hMLH1 and wild-type for p53, and HCT15 cells, which are mutant in hMSH6 and mutant in p53 as well.
Aberrant methylation of the promoter CpG island of hMLH1 is associated with gene silencing in colon cancer and gastric cancer with microsatellite instabilities (MSI).