Early events in colorectal tumorigenesis include mutation of the adenomatous polyposis coli (APC) gene and epigenetic hypermethylation with transcriptional silencing of the O(6)-methylguanine DNA methyltransferase (MGMT), human mut L homologue 1 (hMLH1), and P16/CDKN2A genes.
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.
We suggest that hMLH1 and hMSH3 genes could be involved in lung tumorigenesis through dosage effect in cellular functions other than replication error correction.
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.
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 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.
Previously, we reported that hypermethylation of hMLH1 might play an important role in the tumorigenesis of right-sided sporadic CRCs with MSI showing less frequency of KRAS/TP53 alteration.
Our results support the hypothesis that proximal and distal colorectal tumors with mismatch repair deficiency harbor different genetic alterations, and we suggest that the involvement of the RAS/RAF pathway in colorectal tumorigenesis is differentially modulated according to tumor location and MLH1 inactivation.
Our study demonstrates that inactivation of the DNA mismatch repair genes hMLH1 and hMSH2 does not appear to play a role in the tumorigenesis of pediatric renal cell carcinomas with Xp11.2 rearrangements.
To address whether MLH1 methylation in PBCs is correlated with tumorigenesis we utilized the Illumina 450 K microarrays to measure methylation in PBC DNA of 846 healthy controls and 252 CRC patients from Ontario, Canada.
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.
Therefore, we analyzed aberrant hypermethylation of the hMLH1 gene, microsatellite instability (MSI), and point mutations of KRAS and BRAF in 44 samples of sporadic endo-metrial cancer, with the aim of examining the mechanism of carcinogenesis in patients with endometrial cancer.
Our data confirm previous observations and suggest that losses of the MLH1 and CDKN2 genes and alterations of the TIMP3 gene play an important role in head and neck carcinogenesis.
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.
Promoter hypermethylation of the hMLH1 gene could be detected early in head and neck squamous carcinogenesis and may be associated with increased MSI and poor survival in HNSCC.
Increased age at diagnosis and tumor characteristics of microsatellite unstable tumors associated with MLH1 -93 G>A suggests the polymorphism is acting at a relatively late stage of colorectal carcinogenesis to drive CIMP+ tumors down the microsatellite instability pathway.
Previous work has demonstrated that the <i>villin</i>-<i>Cre<sup>+/-</sup>Msh2<sup>flox/flox</sup></i> (VpC-Msh2) mouse is a reliable model for LS/HNPCC intestinal tumorigenesis, which is significantly suppressed by treatment with the NSAID aspirin (ASA) similar to human chemoprevention.
The present findings suggested that aberrant Fhit and Mlh1 expression could be related to DN carcinogenesis and that P53 overexpression and changes in phenotypic expression could contribute to the malignant transformation of colorectal precursor lesions.