Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic instability of microsatellite repeat sequences [microsatellite instability (MI)] is commonly seen in tumors associated with the hereditary nonpolyposis colorectal cancer syndrome and is a result of inactivating mutations in any of several genes involved in a particular pathway of DNA mismatch repair. Sporadic (i.e., nonhereditary) manifestations of several tumor types, including colorectal, gastric, and endometrial carcinomas, also exhibit MI in a significant fraction of cases. Many MI+ sporadic colorectal carcinomas are associated with somatic mutations of mismatch repair genes, and several genes with coding region microsatellites are frequently mutated as a result in these cancers. The molecular causes and consequences of MI in sporadic endometrial carcinomas remain obscure, however. The aims of this study were: (a) to identify a series of sporadic endometrial carcinomas with clear evidence of MI; (b) to determine the extent to which somatic alterations in mismatch repair genes are associated with this MI; and (c) to establish whether the genes containing coding region microsatellite repeats that are known to be disrupted in MI+ gastrointestinal cancers are also disrupted in MI+ endometrial carcinomas. Matched pairs of normal and tumor DNA from 57 consecutive cases of endometrial carcinoma were examined for evidence of MI using a consensus panel of microsatellite markers. Fourteen cases (25%) displayed unequivocal evidence of MI, consistent with previously published estimates of the incidence of MI+ sporadic endometrial carcinoma. These cases were subjected to a mutation screen of the coding regions and exon-intron boundaries of the mismatch repair genes MSH2 and MLH1. Although several polymorphisms were detected, no clearly deleterious mutations were found in either of these genes. Notably, however, hypermethylation of the MLH1 promoter region was identified in 10 of 14 (71%) MI+ cases. Somatic mutations in coding region microsatellite repeats in the TGFbetaIIR, IGFIIR, BAX, E2F4, MSH3, MSH6, BRCA1, and BRCA2 genes were generally rare. Four MI+ tumors (29%) contained somatic mutations in the PTEN gene, only one of which was likely the result of MI. These data indicate that somatic mutational inactivation of known mismatch repair genes does not account for the great majority of sporadic endometrial carcinomas with MI and that a significant fraction of these cases may instead be causally associated with hypermethylation of the MLH1 promoter. Furthermore, genes with coding region microsatellites that are frequently mutated in MI+ gastrointestinal cancers are rarely mutated in MI+ endometrial cancers, implying the existence of alternative molecular targets for the tumorigenic effects of MI in this tumor type.
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PMID:Causes and consequences of microsatellite instability in endometrial carcinoma. 992 63

Microsatellite instability (MSI) in human carcinoma DNA is a characteristic phenotype observed in hereditary non-polyposis colorectal cancer and also in some human sporadic cancers including multiple primary carcinomas. In this study, we analyzed mutations in the hCHK1, E2F4, hMSH3, and hMSH6 genes in MSI+ human cancers arising in colorectum, stomach and endometrium. The E2F4 and hMSH3 genes were mutated in all tumor types. Interestingly, the hMSH6 gene was mutated in colorectal and gastric cancers but not in endometrial cancer; this is similar to the TGFbetaRII gene. It is notable that the mutation status of the secondary mutators, hMSH3 and hMSH6, did not influence slippage-related frameshift mutations in genes harboring simple tandem-repeats, which suggests that the MSI phenotype may be affected mainly by abnormalities in the primary mutator genes, not by the secondary mutator genes. No mutations were observed in the cell cycle checkpoint gene hCHK1; mutations of this gene are thought to have a limited role, if any, in at least the tumor types analyzed in this study.
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PMID:Analysis of the candidate target genes for mutation in microsatellite instability-positive cancers of the colorectum, stomach, and endometrium. 1071 41

The retinoblastoma family consists of the tumor suppressor nuclear phosphoprotein pRb/p105 and related proteins p107 and pRb2/p130. Recent immunohistochemical studies of the retinoblastoma family of proteins in lung and endometrial cancer and choroidal melanomas show a tight inverse correlation between the histologic grading in the most aggressive tumor types and pRb2/p130 expression. This led us to investigate the role of pRb2/p130 in salivary tumors. We studied the expression of pRb2/p130, p107, E2F4, p27, and PcNA by immunohistochemistry in a panel of 44 salivary gland tumors. We found a direct correlation between the cytoplasmic expression of pRb2/p130 and tumor grading and the presence of metastasis that was highly statistically significant (P < 0.001). Additionally, increased cytoplasmic pRb2/p130 expression was significantly correlated with a decreased probability of survival (P < 0.001). Interestingly, p107 nuclear expression showed a strong direct correlation when compared with the same variables. pRb2/p130 showed the highest percentage of undetectable nuclear levels in the specimens examined and the tightest inverse correlation (P < 0.0001) with both the histologic grading and pCNA expression in malignant salivary tumors. Additionally, E2F4 showed an identical localization pattern as to that of pRb2/p130. These data suggests an important role for pRb2/p130 in the pathogenesis and progression of certain salivary gland cancers.
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PMID:Expression of cell cycle-regulated proteins pRB2/p130, p107, E2F4, p27, and pCNA in salivary gland tumors: prognostic and diagnostic implications. 1586 22