These data imply that relatives of CRC cases with MLH1 methylation may be at increased risk of CRC and stomach cancer and possibly ovarian and liver cancer, suggesting that there may be a heritable factor for CRC and other cancers associated with MLH1 methylation in non-Lynch syndrome CRCs.
Familial adenomatous polyposis (FAP), caused by a mutation in the APC gene, is a colorectal cancer predisposition syndrome associated with several other clinical conditions.
The APC promoter is hypermethylated in 18% of primary sporadic colorectal carcinomas (n = 108) and adenoma (n = 48), and neoplasia with APC methylation fails to express the APC transcript.
Germline mutations in the DNA mismatch repair (MMR) genes MSH2, MSH6, or MLH1 predispose to colorectal cancer (CRC) with an autosomal dominant inheritance pattern.
The risk of colorectal cancer in carriers of such EPCAM deletions is comparable to that of MSH2 mutation carriers, and is in accordance with a high expression of EPCAM in colorectal cancer stem cells.
Consequently, we assessed the methylation status of CDKN2A/p16, MGMT, MLH1 and p14(ARF) in adenomas arising in the Lynch syndrome, a familial colon cancer syndrome caused by MLH1 and MSH2 mutations, to determine if DNA methylation is a "second hit" mechanism in CRC and to characterize the role of DNA methylation in the polyp phase of the Lynch syndrome.
To investigate the effect of wild-type hMLH1 in cellular proliferation, wild-type hMLH1 cDNA was introduced into human colorectal carcinoma cell line HCT116 and human gastric carcinoma cell line SNU-1, each containing a homozygous non-sense mutation at codon 252 and 226 in hMLH1, repectively.
We included a total of 19 MSH2-negative colorectal carcinomas from 14 different patients in whom we were able to perform a complete germ-line analysis.
We investigated the relationship between hMLH1 promoter hypermethylation and MGMT promoter hypermethylation in 110 colorectal cancers using methylation-specific polymerase chain reaction.
We also tested whether other significant genetic or clinical status involved in CRC development, such as APC and TP53 mutations, MSI and TNM-Duke's staging, were related with the observed BRAF- or K-ras associated expression profiles.
MYC gene overexpression was identified recently as a downstream step at the end of the Wnt/APC/beta-catenin pathway dysregulation observed in colorectal cancer (T-C.
BRAF mutation and the loss of MLH1 protein were observed in the colorectal cancer, but not in the other serrated polyps around the colorectal cancer, suggesting that colorectal cancer with microsatellite instability develops rapidly from a specific serrated polyp with distinct molecular properties.
Hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome) is characterized by early occurrence of colorectal malignancies, localization of tumors in the proximal colon, frequency of multiple primaries (both synchronous and metachronous) and an autosomal dominant type of genetic transmission.
In Denmark, the national HNPCC register has been granted an exception to send unsolicited letters with information on hereditary colorectal cancer and an invitation to genetic counseling to members of families with familial and hereditary colorectal cancer.
Loss of expression of p16 was found in 30 % of CRC with methylation of the MLH1 promoter, but its expression was retained in all non-methylated and part of MLH1-methylated tumors (100 % specificity, 30 % sensitivity).
This is the first genetic study of CRC in this region of the world to demonstrate the incidence of MSI, p16 methylation, and hMLH1 and MSH2 expression in the Omani population.
Earlier studies have reported the incidence of BRAF mutations in the range of 5-20% in colorectal carcinomas (CRC) and are predominantly seen in the serrated adenoma-carcinoma pathway characterized by microsatellite instability (MSI-H) and hypermethylation of the MLH1 gene in the setting of the CpG island methylator phenotype (CIMP).