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)

Tissue microarray technology enables the analysis of hundreds of specimens by arranging numerous 0.6-mm tissue core biopsy specimens into a single paraffin block. Validation studies are necessary to evaluate the representativeness of small disks taken from the original tissue. We validated the tissue microarray technology in colorectal carcinoma by analyzing the immunohistochemical expression of proteins involved in the two main pathways of colorectal carcinogenesis: p53 protein for loss of heterozygosity tumors, hMLH1 and hMSH2 proteins for microsatellite instability (MSI) tumors. We compared in 30 colorectal carcinomas (15 MSI(-) and 15 MSI(+)), 8 microarrays disks, and the whole section of the block from which they were derived. Tumoral tissue was present in 95.7% of the microarray disks. The analysis of three disks per case was comparable to the analysis of the whole section in 99.6% (p53), 98.8% (hMLH1), and 99.2% (hMSH2) of cases. In the second part we applied the tissue microarray technology to 263 consecutive cases of colorectal carcinoma, sampled by three cores. We showed that 48.5% overexpressed p53 and 8.7% lost hMLH1 or hMSH2. Tissue microarray technology, validated in colorectal carcinoma, appears as a useful research tool for rapid analysis of the clinical interest of molecular alterations.
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PMID:Tissue microarray technology: validation in colorectal carcinoma and analysis of p53, hMLH1, and hMSH2 immunohistochemical expression. 1280 83

Pancreatic mucinous noncystic (colloid) carcinomas (MNCC) differ from the usual ductal adenocarcinomas in their mucin expression profile and share with many extrapancreatic mucinous carcinomas the expression of MUC2. Because mucinous carcinomas are frequently associated with mutations of the DNA mismatch repair genes, causing them to exhibit the so-called mutator phenotype, we decided to investigate whether MNCCs of the pancreas are characterized by microsatellite instability (MSI). Twelve carcinomas with a mucinous phenotype (8 mucinous noncystic carcinomas, 3 intraductal papillary-mucinous carcinomas with an invasive muconodular component, and 1 ductal adenocarcinoma with an extensive mucinous noncystic component) and 11 ductal adenocarcinomas were immunostained with monoclonal antibodies to the mismatch repair gene products hMLH1, hMSH2, and hMSH6. For MSI analysis, DNA was isolated from microdissected tissue, and five primary microsatellites (BAT 25, BAT 26, D5S346, D17S250, and D2S123) were analyzed. MSI was diagnosed in case a novel allele was found, compared with the normal tissue. The criterion for LOH was a 75% signal reduction. All carcinomas tested exhibited nuclear expression of mismatch repair gene products, except for one MNCC that also showed MSI at the molecular level. The data suggest that pancreatic carcinomas with a mucinous phenotype (MUC2+/MUC1-) do not appear to normally exhibit mutations in the mismatch repair genes and therefore differ in their carcinogenesis from those in other organs.
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PMID:Pancreatic mucinous noncystic (colloid) carcinomas and intraductal papillary mucinous carcinomas are usually microsatellite stable. 1280 58

The high-frequency microsatellite instability (MSI-H) phenotype, frequently identified in hereditary nonpolyposis colorectal cancer (HNPCC), also accounts for approximately 15% of sporadic colorectal cancers. Microsatellite instability (MSI) occurs from the mutational inactivation of the DNA mismatch repair genes, i.e. hMSH2 and hMLH1 in HNPCC, as well as from epigenetic inactivation of hMLH1 in sporadic colorectal tumors. The mutator pathway including microsatellite instability, hMLH1 promoter methylation, and hMSH2 and hMLH1 mutation patterns were identified in 21 sporadic colorectal adenocarcinoma patients younger than 30 yr excluding HNPCC. More than half of tumors showed MSI, with five MSI-H and six MSI-L (low-frequency microsatellite instability). Three of six MSI-H tumors showed the hMLH1 promoter methylation and did not express the hMLH1 protein. On the other hand, all MSI-L and all MSS (microsatellite stable) tumors expressed both hMSH2 and hMLH1 proteins. Two novel mutations, i.e. a missense mutation in hMLH1 and a splice-site alteration in hMSH2, were identified in two patients respectively. Although mutator pathway was implicated in younger-age-onset colorectal carcinogenesis, many tumors appeared to evolve from different genetic events other than hMSH2 and hMLH1 mutations frequently identified in HNPCC.
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PMID:Characterization of mutator pathway in younger-age-onset colorectal adenocarcinomas. 1280 26

Differential microsatellite instability (MSI) in tumour epithelial and stromal compartments has not been well examined for colorectal cancers. Using laser-captured microdissection, separate specimens of these compartments of 40 sporadic colorectal cancers were sampled and MSI was tested with four markers. To examine the relation between the MSI phenotype in the stroma and other genetic events and histopathological features, p53 and K-ras gene mutations were analysed, and the expression of p53, hMLH1, and hMSH2 protein was determined by immunohistochemistry. Microsatellite instability positive results were obtained for both epithelium (34%) and stromal tissue (41%). While MSI in epithelium correlated with differentiation and Dukes' stage, that in stroma demonstrated an inverse relation, being particularly frequent in well-differentiated adenocarcinomas (54%) and Dukes' A lesions (55%). Further, a significant inverse correlation between p53 protein overexpression in the epithelium and MSI in the stroma was found (P=0.02475). The results suggest an alternative pathway of carcinogenesis involving stromal genetic instability in the development of colorectal cancers.
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PMID:Possible alternative carcinogenesis pathway featuring microsatellite instability in colorectal cancer stroma. 1291 83

The study of microsatellite instability (MSI) in cases of severe chronic cholecystitis and gallbladder carcinomas, to cast light on its significance for tumorigenesis, revealed MSI in 9 (30%) of 30 cases of cholecystitis and 7 (41%) of 17 carcinomas, respectively. In addition, 5 (33%) of 15 samples of background mucosa of carcinoma were positive. Respective figures for loss of heterozygosity were 3 (10%) of 30 cases of cholecystitis, 6 (35%) of 17 carcinomas, and 1 (7%) of 15 samples of adjacent nonneoplastic mucosa. No correlation was observed among MSI state, immunohistochemical hMLH1 or hMSH2 expression, and any clinicopathologic factors. MSI was observed not only in gallbladder tumors but also in severe chronic cholecystitis and background mucosa, suggesting that it may have an important role in early-stage gallbladder carcinogenesis.
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PMID:Microsatellite instability in chronic cholecystitis is indicative of an early stage in gallbladder carcinogenesis. 1450 6

The liver fluke infection-associated intrahepatic cholangiocarcinoma (ICC) is a major liver cancer in Northeast Thailand. The molecular basis of this ICC is poorly understood. To address possible roles of the DNA mismatch repair (MMR) system in ICC carcinogenesis, a fluorescence-labeling PCR/laser scanning technique with high sensitivity was employed to analyze genomic instability in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) in 24 fresh and 13 formalin-fixed, paraffin-embedded tissues of ICC and their corresponding normal parts. Microsatellite instability (MSI) was assessed in nDNA, using 12 highly polymorphic loci including 5 Bethesda markers. These loci were mainly related to major MMR genes, hMSH2 and hMLH1. Also 3 (C)n and/or (C)n(A)n repeat instability at 1 noncoding region in the displacement-loop (D-loop) and 2 coding sequences in NADH dehydrogenase subunit 1 and subunit 5 gene in mtDNA were analyzed. MSI was only detected in 1 (2.7%), 6 (16.7%), 1 (2.9%), 1 (2.9%) or 2 (6.3%) out of 37, 36, 35, 35 or 32 cases at BAT-25, D2S123, D3S1611, D11S904 or D17S250, respectively. LOH was found at D3S1298, D3S1561, D5S346 and TP53 in 4 (18.2%) out of 22, 2 (18.2%) out of 11, 6 (33.3%) out of 18 and 3 (12.5%) out of 24 informative cases, respectively. In mtDNA, none except a single case out of the 37 (2.7%) exhibited repeat sequence instability in the D-loop. We conclude that the liver fluke infection-associated ICC in Thailand is classified as low frequency MSI or microsatellite stable type and that DNA MMR system, through hMSH2 and hMLH1 gene mutations, does not play a major role in its carcinogenesis.
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PMID:Infrequent microsatellite instability in liver fluke infection-associated intrahepatic cholangiocarcinomas from Thailand. 1450 36

To clarify the genetic background of ampullary neoplasm, we investigated the occurrence of microsatellite instability (MSI) in 64 samples of neoplasm of the ampulla of Vater. Eight out of 22 adenomas (34.6%), nine out of 32 carcinomas (28.1%) and one metastatic lesion (10.0%) showed MSI in 1-3 of the nine dinucleotide markers; those cases are categorized into microsatellite instability-low (MSI-L). The remaining samples were stable with respect to all of the tested markers. None of the samples showed a frameshift mutation in the poly A-tract of BAT-26 or transforming growth factor-beta type II receptor, which are frequently mutated in gastric or colorectal cancers showing microsatellite instability. To confirm our finding, we stained 93 ampullary neoplasms with antibodies against the mismatch repair proteins: hMLH1 and hMSH2. All tumors were found to express mismatch repair proteins. In contrast to gastric or colorectal cancers, MSI does not play an important role in the carcinogenesis of ampullary carcinoma.
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PMID:Lack of microsatellite instability in neoplasms of ampulla of Vater. 1451 16

Microsatellite instability and loss of heterozygosity has been implicated in ovarian carcinogenesis. The reported frequency of microsatellite instability in human ovarian cancer varies significantly owing to the use of heterogeneous tumor histotypes and various microsatellite markers in different laboratories. In this study, we determined the frequency of microsatellite instability in 74 ovarian endometrioid carcinomas using four microsatellite markers (BAT25, BAT26, D5S346, D17S250), and examined hMLH1 and hMSH2 protein expression. In all, 20% of the tumors were microsatellite instability high (two or more markers showing instability) and 12% were microsatellite instability low (one marker showed instability). Loss of hMLH1 and/or hMSH2 expression was found in nine of 15 microsatellite instability-high tumors. The microsatellite instability-high phenotype tended to occur more frequently in low-grade tumors (P=0.053), but did not correlate with clinical stage. Totally, 38% of cases also displayed loss of heterozygosity at D17S250; this loss of heterozygosity was associated with high clinical stage (P=0.097). Our results indicate that both microsatellite and loss of heterozygosity at D17S250 are involved in the development of ovarian endometrioid carcinoma.
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PMID:Microsatellite instability and expression of hMLH1 and hMSH2 proteins in ovarian endometrioid cancer. 1463 66

Activating mutations of BRAF have been frequently observed in microsatellite unstable (MSI+) colorectal carcinomas (CRCs), in which mutations of BRAF and KRAS are mutually exclusive. 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. Therefore, we have assumed that BRAF mutations might be highly associated with hMLH1 methylation status rather than MSI status. In this study, mutations of BRAF and KRAS and their relationship with MSI and hMLH1 methylation status were examined in 140 resected specimens of CRC. The methylation status was classified into 3 types: full methylation (FM), partial methylation (PM) and nonmethylation (NM). Only FM closely linked to reduced expression of hMLH1 protein. BRAF mutations were found in 16 cases (11%), all leading to the production of BRAF(V599E). As for MSI status, BRAF mutations were found in 43% of MSI+ and 4% of MSI- cases (p < 0.0001). Among the MSI+ individuals, BRAF mutations were more frequent in cases with hMLH1 deficiency (58%) than those with hMSH2 deficiency (0%; p=0.02). Moreover, they were found in 69% of FM, 4% of PM and 4% of NM, revealing a striking difference between FM and the other 2 groups (FM vs. PM or NM; p < 0.0001). These findings suggest that BRAF activation may participate in the carcinogenesis of sporadic CRCs with hMLH1 hypermethylation in the proximal colon, independently of KRAS activation.
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PMID:Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas. 1463 9

Microsatellite instability (MSI) occurs in 10-20% of the sporadic colon carcinomas and appears to be primarily due to alterations in hMLH1 and hMSH2. Little is known about the role of diet in MSI-related colon carcinogenesis. We used data from a Dutch population-based case-control study on sporadic colon carcinomas (184 cases and 259 controls) to evaluate associations between dietary factors previously reported as being associated with colon cancer risk and MSI, hMLH1 expression, and hMLH1 hypermethylation. Red meat intake was significantly differently related to microsatellite instability-high (MSI-H) tumors compared with microsatellite instability-low/microsatellite stable (MSI-L/MSS) [odds ratio (OR), 0.3; 95% confidence interval (CI), 0.1-0.9]. It was inversely associated with MSI-H tumors when compared with the population-based controls (OR, 0.5; 95% CI, 0.2-1.2) and positively associated with MSI-L/MSS tumors (OR, 1.5; 95% CI, 0.9-2.6). A positive association was observed for alcohol intake with MSI-H tumors (OR, 1.9; 95% CI, 0.8-4.7). Fruit consumption seemed to especially decrease the risk of MSI-H tumors with hypermethylated hMLH1 (Methyl(+) tumors) [Methyl(+) versus controls: OR = 0.4 and 95% CI = 0.2-0.9; MSI-H tumors without hypermethylated hMLH1 (Methyl(-) tumors) versus controls, OR = 1.2 and 95% CI = 0.8-1.7; Methyl(+) versus Methyl(-) tumors, OR = 0.2 and 95% CI = 0.1-0.9]. Most other evaluated dietary factors were not distinctively associated with a specific MSI or hMLH1 methylation status. Our data suggest that red meat consumption may enhance the development of MSI-L/MSS carcinomas in particular, whereas alcohol intake appears to increase the risk of MSI-H tumors. Fruit consumption may especially decrease the risk of MSI-H carcinomas exhibiting epigenetically silenced hMLH1.
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PMID:Dietary factors and microsatellite instability in sporadic colon carcinomas. 1465 71


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