Our results suggest that loss of MLH1 expression in non-dysplastic crypts in SSAs precedes the development of MLH1-deficient dysplasia and adenocarcinoma, and may be a biomarker of an advanced serrated polyp even in the absence of dysplasia.
We classified a cohort of 349 successive gastric adenocarcinomas into 5 subtypes, on the basis of protein or mRNA expression of MLH1, E-cadherin, p53, and Epstein-Barr virus.
We previously developed a novel tumor subtype classification model for duodenal adenocarcinomas based on a combination of the CpG island methylator phenotype (CIMP) and MLH1 methylation status.
These polyps contain BRAF mutations and are prone to epigenetic methylation that ultimately silences MLH1, leading to MSI and heralding progression of dysplasia to invasive adenocarcinoma.
This raises the question whether these morphological subtypes should be maintained or whether an alternative classification of poorly differentiated colorectal adenocarcinomas based on MLH-1 status rather than morphology should be suggested.
This retrospective study included 40 squamous cell carcinomas and 40 adenocarcinomas in various surgical TNM stages to define methylation profile and possible silencing of DNA repair genes - MLH1 and MSH2 - using Methylation-Specific PCR and protein expression by immunohistochemistry in tumoural tissue, preneoplastic lesions and respiratory epithelium with normal histological features.
hMLH1 and hMSH2 mRNA expression was previously evaluated by qPCR for 29 NSCLC patients (13 with squamous cell carcinoma [SQC] and 16 with adenocarcinoma [ADC]) and MMR mRNA levels were converted into clinically distinct phenotypic entities.
CIMP(+) was detected in 27 of 99 (27.3%) duodenal adenocarcinomas and was associated with MSI (P = 0.011) and MLH1 methylation (P < 0.001), but not with KRAS mutations (P = 0.114), as compared with CIMP(-) tumors.No BRAF V600E mutation was detected.
SFRP2 and IGF2 DMR0 showed significant methylation changes at the adenomatous polyp stage, followed by the CIMP markers CDKN2A and hMLH1 at the adenocarcinoma stage.
KRAS codon 12/13 and 59/61 and BRAF V600E mutations, MSI, and MGMT and hMLH1 methylation and expression in 42 serrated adenocarcinomas and 17 serrated adenomas were compared with those in 59 non-serrated colorectal carcinomas (CRCs) and nine adenomas.
To verify the methylation status of CDH1, DAPK, COX2, hMLH1 and CDKN2A genes and to evaluate their association with Helicobacter pylori (H. pylori)-cagA(+) and Epstein Barr virus (EBV) infections in gastric adenocarcinomas.
Methylation of hMLH1 is likely to explain the increased frequency of high-level MSI (16%) and methylation of MGMT is postulated to explain the low-level MSI (29%) in serrated adenocarcinomas.
Loss of MLH-1 (25%) or MGMT (50%) expression and BRAF or KRAS mutations (50%) were inconsistently present in adenocarcinomas and were not identified in combination in any cases.
These results suggest that microsatellite-unstable mucinous carcinoma occurring in the elderly shares clinicopathological and molecular features with medullary type poorly differentiated adenocarcinoma and that microsatellite instability with absent hMLH1 expression plays an important role in the development of these two carcinomas.
These results suggest that microsatellite-unstable mucinous carcinoma occurring in the elderly shares clinicopathological and molecular features with medullary type poorly differentiated adenocarcinoma and that microsatellite instability with absent hMLH1 expression plays an important role in the development of these two carcinomas.
These results indicate that an age-related increase of medullary-type tumors in poorly differentiated adenocarcinoma may play an important role in the increase of absent hMLH1 expression and MSI in colorectal carcinoma.