In order to better understand the role of somatic and germline alterations within hMSH2 and hMLH1 in the process of colorectal tumorigenesis, we examined the entire coding regions of both of these genes in seven patients with MIN+ sporadic colorectal cancer, 19 patients with familial colorectal cancer, and 20 patients meeting the strict Amsterdam criteria for HNPCC.
Evidence supporting the role of MMR defects in carcinogenesis comes from a variety of independent sources including: (i) theoretical considerations of the requirement for a mutator phenotype as a step in multistage carcinogenesis; (ii) discovering that MMR defects cause a 'mutator phenotype' destabilizing endogenous expressed genes including those integral to carcinogenesis; (iii) finding MMR defects in the germline of HNPCC kindred members; (iv) finding that such defects behave as classic tumor suppressor genes in both familial and sporadic colorectal cancers; (v) discovering that MMR 'knockout' mice have an increased incidence of tumors; and (vi) discovering that genetic complementation of MMR defective cells stabilizes the MMR deficiency-associated microsatellite instability.
This suggests that defects in the mismatch repair gene hMLH1 at 3p21 may be involved in microsatellite instability and tumorigenesis of a subset of nonsmall cell lung carcinomas.
We suggest that hMLH1 and hMSH3 genes could be involved in lung tumorigenesis through dosage effect in cellular functions other than replication error correction.
Loss of heterozygosity at hMSH2 and/or hMLH1 gene loci, and the associated microsatellite instability in premalignant hepatic tissues suggests a possible causal role in hepatic carcinogenesis in a subset of hepatomas.
To determine whether hMLH1 promoter hypermethylation is a relatively early event in endometrial tumorigenesis we evaluated endometrial hyperplasia (EH) characterized as simple, complex, and atypical (the direct precursor of endometrial carcinoma) for hMLH1 aberrant methylation.
Our results suggest firstly that the hMSH2 gene plays a much more important role than hMLH1 in the carcinogenesis of Japanese HNPCC patients, secondly that the rate of hMSH2 and hMLH1 mutations is high in the kindreds satisfying the Amsterdam criteria and thirdly that both the clinical phenotypes (early onset, vertical transmission and multiplicity of tumors) and the microsatellite instability status are important for the genetic screening of HNPCC.
These data confirm that functional deficiencies in the interaction of hMLH1 with hPMS2 are associated with HNPCC as well as suggest that other unknown functional alteration of the human MutL homologues may lead to tumorigenesis in HNPCC kindreds.
We were prompted by our previous finding of 43% of cervical cancers and their precursors with a loss of heterozygosity (LOH) of the hMLH1 gene to investigate whether it is inactivated during the carcinogenesis of cervical cancer.
Our data suggest that MI plays a significant role in non-small cell lung cancer tumorigenesis in Taiwan and that MI is associated with the altered expression of hMLH1 mismatch repair protein.
On the other hand, reduced expression level of BARD1, and of hMSH2 and hMLH1, which are components of DNA mismatch-repair pathway and are involved in colorectal carcinogenesis, was observed respectively in only 10 (6%), 8 (5%) and 3 (2%) cases.
To determine the frequency and timing of hypermethylation during multistep gastric carcinogenesis, non-neoplastic gastric mucosa (n = 118), adenomas (n = 61), and carcinomas (n = 64) were analyzed for their p16, human Mut L homologue 1 (hMLH1), death-associated protein (DAP)-kinase, thromobospondin-1 (THBS1), and tissue inhibitor of metalloproteinase 3 (TIMP-3) methylation status using methylation-specific PCR.
The gastrointestinal carcinogenesis is suggested to be associated with the decrease of total genomic DNA methylation; hypomethylation of certain specific oncogenes such as c-myc, c-Ha-ras, c-fos and alpha-fetoprotein; and hypermethylation of the promoter of some tumor suppressor genes containing p16(INK4A), E-cadherin and hMLH1 genes.
A high incidence of defective MSH2 and MLH1 protein in endometrial carcinoma with multiple primary carcinomas, however, suggests that abnormalities in the function of MSH2 and MLH1 may play an important role in tumorigenesis for patients with endometrial carcinoma with multiple primary carcinomas and their families.