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)

To determine the relation between the mutation of the TGF-beta type II receptor gene and genomic instability in the tumorigenesis of hereditary nonpolyposis colorectal cancer (HNPCC), we screened genomic DNA of 38 tumors from 25 HNPCC patients, 15 colorectal cancers from familial adenomatous polyposis patients, and 8 sporadic endometrial cancers, in two areas containing a (A)10 repeat or a (GT)3 repeat of the gene. Seventeen of the 24 (71%) genomic instability-positive HNPCC tumors carried one or two A deletions in the (A)10 repeat, while none of the 14 genomic instability-negative tumors did. These deletions inactivate the receptor through a frameshift mutation and the resultant protein truncation. No mutation was detected in the (GT)3 repeat sequence, but we found a missense mutation of codon 537 in the same area in one tumor. One A deletion was also detected in a genomic instability-positive sporadic endometrial cancer, but none in familial adenomatous polyposis tumors. No mutations were detected in the corresponding normal cells of these cases, indicating a somatic mutation. These data suggest that the TGF-beta type II receptor gene is a major target of genomic instability in HNPCC tumorigenesis.
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PMID:Mutations of the transforming growth factor-beta type II receptor gene and genomic instability in hereditary nonpolyposis colorectal cancer. 748 33

The majority of tumors from hereditary nonpolyposis colorectal cancer families and a subset of unselected gastrointestinal and endometrial tumors exhibit a microsatellite mutator phenotype (MMP) that leads to the accumulation of hundreds of thousands of clonal mutations in simple repeat sequences. The mutated genes with positive or negative roles in cell growth or survival in aneuploid gastrointestinal cancer (e.g., APC, K-ras, and p53) are less frequently mutated in near-diploid MMP gastrointestinal tumors. These tumors accumulate mutations in other genes, such as DNA mismatch repair hMSH3 and hMSH6, transforming growth factor-beta type II receptor, and BAX. All these genes carry, within their coding sequences, mononucleotide repeats that are preferred targets for the MMP. Endometrial carcinoma is the most common type of extracolonic neoplasia in the hereditary nonpolyposis colorectal cancer syndrome, but the spectrum of its target cancer genes is not well characterized. Here, we report that endometrial cancer of the MMP also accumulates mutations in genes that are typically mutated in gastrointestinal cancer of the mutator pathway, including BAX (55%), hMSH3 (28%), and hMSH6 (17%). We also report the detection of frameshift mutations in caspase-5, a member of the caspase family of proteases that has an (A)10 repeat within its coding region, in MMP tumors of the endometrium, colon, and stomach (28, 62, and 44%, respectively). We therefore suggest caspase-5 as a new target gene in the microsatellite mutator pathway for cancer.
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PMID:Frameshift mutations at mononucleotide repeats in caspase-5 and other target genes in endometrial and gastrointestinal cancer of the microsatellite mutator phenotype. 1038 66

Cellular responses to the transforming growth factor beta (TGFbeta) ligand, including inhibition of cell proliferation, are mediated by a heteromeric receptor complex composed of TGFbeta types I and II receptors (TbetaR-I and TbetaR-II). Loss of responsiveness to TGFbeta, attributed to inactivation of the TbetaR complex, has been implicated in the development of tumors in a number of human epithelial and lymphoid tissues. To gain a better understanding of TGFbeta signal transduction pathways in endometrial carcinogenesis, we have investigated the role of the TbetaR complex by evaluating the TbetaR-I and TbetaR-II genes for mutations throughout the entire coding region in human sporadic endometrial tumors. Using reverse transcription-PCR, "Cold" single-strand conformation polymorphism analysis, and direct DNA sequencing, it was found that 1 of 39 (2.6%) and 7 of 42 samples (17%) contained code-altering changes in the kinase domain of TbetaR-I and TbetaR-II, respectively. In 7betaR-I, a 3-bp deletion was found resulting in replacement of Arg and Glu at codon 237 and 238 by Lys. With TbetaR-II, mutations were found in the kinase, the extracellular, and the C-terminal domains. No frameshift mutations were detected; however, a silent population polymorphism (AAC-->AAT at codon 389) in TbetaR-II was found in 19 of 42 (44%) tumor samples. These results suggest that alteration in TbetaR-II, but not TbetaR-I, has an important role in the development of endometrial carcinoma.
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PMID:Genetic alterations in the transforming growth factor receptor complex in sporadic endometrial carcinoma. 1094 82

Microsatellite instability (MSI) and loss of heterozygosity (LOH) were examined in 60 cases of uterine endometrial adenocarcinoma, using 13 microsatellite markers. In non-Smad-related regions, MSI and LOH were noted in 13 of 60 (21.7%) and in 20 of 60 (33.3%) cases, respectively. Genetic alternation of TGF-beta RII was noted in 1 of 60 cases (1.7%). The frequency of MSI and LOH was highest in Stages III and IV, respectively. Cases with G2 carcinoma showed the highest frequency, but LOH frequency did not differ among G1, G2, and G3 carcinoma cases. In Smad-related microsatellite regions, MSI and LOH were noted in 10 of 60 (16.7%) and in 12 of 60 (20.0%) cases, respectively. The frequency of MSI and LOH was highest in Stages III and IV, respectively. LOH was seen only in the Smad2 gene but not in the Smad4 gene. Our results suggest that the alterations in MSI and LOH were associated with middle and late stages of carcinogenesis of endometrial carcinoma. Both MSI and LOH tended to show an association with moderate to severe atypia of carcinoma. Our results also suggest that genetic alteration of the Smad2 gene is more responsible for endometrial carcinogenesis than that of the Smad4 gene. However, the TGF-beta type II receptor gene was considered a minor target of genetic instability in endometrial carcinogenesis.
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PMID:Analysis of microsatellite instability and loss of heterozygosity in uterine endometrial adenocarcinoma. 1137 4

Transforming growth factor-beta (TGF-beta) belongs to a superfamily of structurally related polypeptides involved in various biological processes, including cell growth, proliferation and differentiation, angiogenesis, apoptosis, and extracellular matrix remodeling. We tried to define the different expression patterns of the TGF-beta receptors by investigating the female reproductive organs during the menstrual cycle and endometrial tumorigenesis, because their role in these processes is still unclear. In this study, we examined the expression of the TGF-beta type I and type II receptors in normal (n=13) and carcinomatous (n=42) endometrial tissue specimens using reverse transcriptase polymerase chain reaction and immunological (Western blot and enzyme linked immunosorbent assay) methods. Two uncommon female genital tract tumors, rhabdomyosarcoma of the uterine cervix and uterine carcinosarcoma, were also included. There were no significant differences between normal and cancerous endometrial tissues regarding the TGF-beta receptors mRNA levels. However, we observed a markedly low TGF-beta type I receptor protein level (P<0.028; Mann-Whitney-U test), while the malignant endometrium showed a significantly higher TGF-beta type II receptor protein level (P<0.007; Mann-Whitney-U test) than the normal endometrium. Moreover, significantly elevated TGF-beta receptor type II protein level was noted when depth of myometrial invasion of endometrial carcinomas was considered (P<0.05; Mann-Whitney-U test). In contrast to uterine carcinosarcoma, in which no detectable mRNA for TGF-beta type II receptor was found, we noted expression of both TGF-beta receptors in rhabdomyosarcoma of the uterine cervix. However, neither rhabdomyosarcoma of the uterine cervix nor uterine carcinosarcoma displayed TGFbetaRI and TGFbetaRII protein expression. This observation corroborates the complexity of the deregulation of TGF-beta receptor expression in human endometrial cancer.
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PMID:Expression of TGF-beta type I and II receptors in normal and cancerous human endometrium. 1221 93