Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Silencing of the MLH1 gene by promoter hypermethylation is the mechanism underlying the microsatellite instability (MSI) phenotype in endometrial cancers. However, the profile of CpG methylation in a wide range of MLH1 promoters in endometrial cancers and in the normal endometrium is largely unknown. The present study investigates the region 700 bp upstream of MLH1 covering 48 CpG sites using bisulfite sequencing. Methylation status was classified as full (over 80% of CpGs are methylated), partial (10-80%) or nonmethylation (less than 10%). Of 56 endometrioid endometrial cancers, 16 (29%) were fully methylated, 14 (25%) were partially methylated and 26 (46%) were not methylated. Analyses of MLH1 by immunohistochemical means and of MSI revealed that the degree, rather than region-specific methylation of CpG islands is critical for decreased MLH1 expression and the MSI phenotype. Among 12 patients with methylated cancers, five (42%) patients contained methylated promoters in their normal endometria with profiles similar to those of cancer lesions, and these were associated with the MSI phenotype. In contrast, only one of 31 (3%) normal endometria from patients without endometrial malignancies harbored methylated promoters. These findings suggest that hypermethylation of the MLH1 promoter is frequent in the histologically normal endometrium adjacent to cancers, supporting the notion that hypermethylation of mismatch repair genes is the initial step that triggers various genetic events in endometrial carcinogenesis.
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PMID:Frequent hypermethylation of MLH1 promoter in normal endometrium of patients with endometrial cancers. 1270 Jun 70

In order to evaluate the hereditary background of endometrial hyperplasia patients in relation to protein expression of DNA mismatch repair genes, we evaluated 69 patients with endometrial hyperplasia and 18 patients with normal endometrium having both a personal and family history of cancer (two hereditary nonpolypoid colorectal cancer (HNPCC) patients). We obtained personal and family histories of cancer for all patients. MSH2 and MLH1 protein expression was investigated by immunohistochemical methods. In the endometrial hyperplasia patients, 11 had personal histories and 40 had family histories of cancer. Among the 11 endometrial hyperplasia patients with a personal history of cancer, most cancers were breast or colorectal cancers (82%). In the 40 patients with a family history of cancer, colorectal cancer (33%) was the most frequent. The incidence of loss of expression of MSH2 and/or MLH1 protein in endometrial hyperplasia patients with personal (64%) or family (40%) histories was significantly higher than that in patients without such history (no personal: 21% and no family: 10%; P = 0.0035 and 0.0065). No protein loss was detected in any of the cases with normal endometrium having either a personal or family history of cancer. Our results suggest that a portion of endometrial hyperplasia cases having a personal or family history of cancer may belong to HNPCC, and that in these cases, abnormality of the mismatch repair system may be an early event in endometrial carcinogenesis.
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PMID:Cancer history and loss of MSH2 and MLH1 protein expression in patients with endometrial hyperplasia. 1280 Dec 68

Loss of heterozygosity (LOH) and microsatellite instability (MSI) have been recognized as important events in squamous cell carcinoma of the head and neck (HNSCC), suggesting involvement of both suppressor and mutator pathways. We analyzed 153 HNSCC with 8 Bethesda reference panel markers and 14 microsatellite markers selected from chromosomal regions known to harbor either tumor-suppressor genes or oncogenes. A combination of multiplex fluorescence-based polymerase chain reaction and automatic fragment analysis was performed. LOH was observed in 78% of all tumors. 2% to 17% LOH frequency was observed with Bethesda reference panel markers comparing to higher 8% to 48% LOH in chromosomal areas 3p, 9p, 11q, and 17p. LOH of 11q14.3 correlated with tumor grade. The proportions of high- and low-MSI tumors were 3% and 10%, respectively, but no mutation was identified in MLH1 and MSH2 mismatch repair genes. These results indicate the dominant role of the suppressor in comparison with the mutator pathway in HNSCC carcinogenesis.
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PMID:Low microsatellite instability and high loss of heterozygosity rates indicate dominant role of the suppressor pathway in squamous cell carcinoma of head and neck and loss of heterozygosity of 11q14.3 correlates with tumor grade. 1449 93

Topics discussed here include PTEN mutations and colonic polyps; WNT signaling, APC, beta-catenin, and gastrointestinal neoplasms; mismatch-repair genes (MLH1, MSH2, PMS1, MSH6) and hereditary nonpolyposis colorectal cancer; MYH mutations and autosomal recessive colorectal tumors; STK11 mutations and Peutz-Jeghers syndrome; TGFbeta and gastrointestinal cancer; BMPR1A mutations and juvenile polyposis; FGF/FGFR alterations in gastrointestinal neoplasms; PTCH mutations and gastrointestinal neoplasms; RUNX3 expression and gastric cancer; role of mucins in gastric carcinogenesis; KIT, PDGFRalpha, and gastrointestinal stromal tumors; intestinal neurofibromatosis; and gastrointestinal tumors in other disorders.
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PMID:Molecular dimensions of gastrointestinal tumors: some thoughts for digestion. 1451 68

A case-control study of Filipino patients who underwent surgical resection for colorectal cancer (CRC) during a 1-year period was undertaken. Thirty-five patients under age 40 years were identified. Paraffin blocks of these and 35 randomly selected patients over age 40 underwent histologic and immunohistochemical evaluation. Markers chosen for evaluation included the apoptosis-associated gene products (p53 and bcl-2), a tumor proliferation activity-related factor (Ki-67), and the markers (MLH1 and MSH2) of DNA microsatellite instability (MSI). Results were correlated with age and the stage and location of the tumor. The average age of the early-onset group was 30.7 years compared to the late-onset group at 67.0 years; and the male/female ratio was equivalent. The younger patients had a significantly higher Dukes' stage, the tumors were more poorly differentiated, and they were more frequently of the mucinous and signet ring cell histopathologic type. Expression of p53 was higher in the younger patients ( p < 0.001) and was independent of the degree of differentiation or the stage of the tumor. No differences of expression were noted for the other markers measured. The increased frequency of CRC in Filipino patients less than 40 years of age offers a unique opportunity to gain a better understanding of carcinogenesis, which might be exploited during diagnosis and management. The differences noted between the early- and late-onset CRC are provocative and provide an impetus for increased screening in Filipinos.
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PMID:Clinical and molecular biologic characteristics of early-onset versus late-onset colorectal carcinoma in Filipinos. 1470 47

Hypermethylation of cytosine residues in the CpG islands of tumor suppressor genes is a key mechanism of colorectal carcinogenesis. Detection and quantification of CpG island methylation in human DNA isolated from stools might provide a novel strategy for the detection and investigation of colorectal neoplasia. To explore the feasibility of this approach, colorectal biopsies and fecal samples were obtained from 32 patients attending for colonoscopy or surgery, who were found to have adenomatous polyps, colorectal cancer, or no evidence of neoplasia. A further 18 fecal samples were obtained from healthy volunteers, with no bowel symptoms. Isolated DNA was modified with sodium bisulfite and analyzed by methylation-specific PCR and combined bisulfite restriction analysis for CpG island methylation of ESR1, MGMT, HPP1, p16(INK4a), APC, and MLH1. CpG island methylation was readily detectable in both mucosal and fecal DNA with methylation-specific PCR. Using combined bisulfite restriction analysis, it was established that, in volunteers from whom biopsies were available, the levels of methylation at two CpG sites within ESR1 assayed using fecal DNA were significantly correlated with methylation in DNA from colorectal mucosa. Thus, noninvasive techniques can be used to obtain quantitative information about the level of CpG island methylation in human colorectal mucosa. The methods described here could be applied to a much expanded range of genes and may be valuable both for screening purposes and to provide greater insight into the functional consequences of epigenetic changes in the colorectal mucosa of free-living individuals.
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PMID:Use of DNA from human stools to detect aberrant CpG island methylation of genes implicated in colorectal cancer. 1534 51

Microsatellite instability (MSI) is a well-recognized phenomenon that is classically a feature of tumors in the hereditary non-polyposis colorectal syndrome. Ten to 15% of sporadic colorectal cancers, however, will have MSI. Microsatellite unstable tumors can be divided into two distinct MSI phenotypes: MSI-high (MSI-H) and MSI-low (MSI-L). MSI sporadic colorectal cancers with a high level of MSI (MSI-H) form a well defined group with distinct clinicopathologic features characterized by an overall better long-term prognosis. These sporadic MSI-H colorectal tumors most often arise from the epigenetic silencing of the mismatch repair gene MLH1. In contrast, MSI-L colorectal tumors have not been shown to differ in their clinicopathologic features or in most molecular features from microsatellite stable (MSS) tumors. Unlike MSI-H tumors, MSI-L tumors appear to arise through the chromosomal instability carcinogenesis pathway, similar to MSS tumors. Some groups have reported more frequent mutations in K-ras and in the methylation of methylguanine transferase in MSI-L tumors, but others have questioned these findings. Therefore, although the use of the MSI-L category is widespread, there continues to be some debate as to whether a discrete MSI-L group truly exists. Rather, it has been suggested that MSI-L tumors differ quantitatively from MSS tumors but do not differ qualitatively. Future studies will need to evaluate the specific mutations in non-MSI-H tumors in an attempt to sub-classify MSI-L tumors with regard to MSS tumors so that subtle differences between these two sub-groups can be identified.
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PMID:Colorectal carcinogenesis: MSI-H versus MSI-L. 1552 85

Aberrant methylation is a main mechanism of tumor suppressor gene inactivation in carcinogenesis. In this study, the methylation status of RASSF1A, p16, MLH1, MSH2 and ERalpha was investigated in 84 primary soft tissue sarcomas (STSs), including 22 liposarcomas, 18 malignant fibrous histiocytomas (MFHs), 18 leiomyosarcomas, 6 rhabdomyosarcomas, 6 neurogenic sarcomas and several other sarcoma entities. RASSF1A hypermethylation was detected in 17 of 84 (20%) STSs; however, methylation was more frequent in leiomyosarcomas (39%) compared to MFHs (6%; p < 0.015) and liposarcomas (18%). The p16 CpG island was methylated in 22 out of 82 (27%) cases. In 7 out of 81 (9%) STS samples, the promoter of MLH1 was methylated and in liposarcoma the methylation frequency was higher (14%). For MSH2, no hypermethylation was detected. Methylation of ERalpha was detected in 48 of 63 (76%) STSs, but also in 4 of 8 (50%) normal tissue samples. Furthermore, we analyzed mutational activation of K-ras and BRAF. In 4 out of 84 (5%) of STSs, a substitution at codon 599 of BRAF was found; however, no alteration of K-ras was detected. In an univariate Cox proportional-hazards regression model, we found that the risk of a tumor-related death for STS patients with methylated RASSF1A was significantly increased (RR = 2.9; p = 0.037). In summary, our data indicate that inactivation of RASSF1A is a common event in STS, especially in leiomyosarcoma. Thus, the methylation status of cancer-related genes was distinct in different STS and methylation of RASSF1A promoter can serve as prognostic marker in STSs.
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PMID:Alterations of cancer-related genes in soft tissue sarcomas: hypermethylation of RASSF1A is frequently detected in leiomyosarcoma and associated with poor prognosis in sarcoma. 1555 6

The molecular background of sporadic endometrial cancer coexisting with colorectal or breast cancer is not clear. We investigated microsatellite instability (MSI) and status of mismatch repair (MMR) gene product, MLH1, MSH2 and MSH6, in 63 sporadic endometrial cancers coexisting with colorectal or breast cancer. Sixteen sporadic endometrial cancers with colorectal cancers (EC), 26 sporadic endometrial cancers with breast cancer (EB) and 21 endometrial cancers without a coexisting cancer (control) were analyzed. EC had the highest frequency of MSI among the 3 groups (EC, 69%; EB, 23%; and control, 43%). Incidence of low-frequency MSI was significantly higher in EC (38%). Among endometrial cancer cases diagnosed before age 50, all high-frequency MSI (MSI-H) cases belonged to EC. Interestingly, incidence of MSI-H was significantly higher in tamoxifen-non-treated cases (75%) than that of treated cases (14%). These results suggest that alterations in MMR genes appear to be involved in carcinogenesis of EC but seem to be uncommon in those of EB. Presence of MSI in sporadic endometrial cancer may be a useful marker to predict the risk of colorectal cancer.
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PMID:Microsatellite instability and expression of mismatch repair genes in sporadic endometrial cancer coexisting with colorectal or breast cancer. 1558 95

A subset of sporadic colon cancers has been shown to have microsatellite instability caused by an epigenetic inactivation of the MLH1 gene by hypermethylation of the the CpG island in its promoter region. We report here that in colorectal cancer, inactivation of the MLH1 gene is frequently accompanied by hypermethylation of the CpG island in the promoter of the mitotic gene checkpoint with forkhead and ring finger domains (CHFR). This was first observed in the colon cancer cell lines HCT-116, DLD-1, RKO and HT29. Among the 61 primary colon cancer samples studied, hypermethylation of the MLH1 and the CHFR promoter was found in 31% of the tumors. In 68% of all primary cancers (13/19) with MLH1 promoter hypermethylation, hypermethylation of the CHFR promoter was observed as well (P-value < 0.0001, Fisher's two-sided exact). Hypermethylation of the HLTF, MGMT, RASSF1, APC, p14 and p16 promoter regions were also frequent events, being observed in 48% (28/58), 40% (26/64), 21% (14/64), 50% (31/62), 43% (26/60) and 56% (35/63), respectively. However, methylation of these genes was not associated with methylation of either MLH1 or CHFR. The observed methylation profile was unrelated to Duke's stage. The coordinated loss of both mismatch repair caused by methylation of MLH1 and loss of checkpoint control associated with methylation of CHFR suggests the potential to overcome cell cycle checkpoints, which may lead to an accumulation of mutations.
Carcinogenesis 2005 Jun
PMID:CHFR promoter hypermethylation in colon cancer correlates with the microsatellite instability phenotype. 1576 Sep 19


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