Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An Egyptian hospital-based pilot case-control study was conducted to investigate the relationship between the expression level of mismatch repair (MMR) genes and the risk of colorectal cancer. The relative expression of five known MMR genes, i.e., hMSH2, hMLH1, hPMS1, hPMS2, and GTBP/hMSH6, was measured by a multiplex reverse transcriptase (RT)-polymerase chain reaction (PCR) in peripheral blood lymphocytes from 31 colorectal cancer patients and 47 age- and-sex matched controls. The expression of hMSH2, GTBP/hMSH6, hPMS1 and hPMS2 tended to be lower in patients than controls, but only the difference in hPMS2 expression was statistically significant (p<0. 01). Although 50% of the cases had chemotherapy or radiotherapy within the last six months before the blood was drawn, their gene expression was not statistically different from those who had not undergone such therapies. After adjustment for age and sex, the odds ratios (OR) calculated from a logistical regression model, using the median levels of gene expression of controls as cut-off values, indicated that increased risk was associated with reduced expressions of both hPMS1 (OR = 3.97, 95% confidence interval (CI) = 1.04 to 7.65) and hPMS2 (OR = 2.86, 95% CI = 1.05 to 7.76). Although the results of this study were inconclusive because of the small sample size and use of prevalent cases, it is biologically plausible that patients with colorectal cancers may have a lower expression of MMR genes than healthy controls because malfunction of these genes has been shown in hereditary nonpolyposis colon cancer. The involvement of low hPMS2 expression in colon cancer risk seems to be unique in the Egyptian population. Further studies with newly diagnosed patients before they begin therapy will provide more convincing data about the role of MMR gene expression in the etiology of colorectal cancers in Egypt.
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PMID:Reduced expression of mismatch repair genes in colorectal cancer patients in Egypt. 959 92

Hereditary non-polyposis colorectal cancer (HNPCC), or Lynch syndrome I, is responsible for as high as 10% of all colorectal cancers (CRCs) newly diagnosed in any given year. This disorder has an autosomal dominant inheritance pattern and is almost fully penetrant (>85%). It occurs when there is a mutation in any one of six mismatch repair genes: hMLH1, hMSH2, hPMS1, hPMS2, hMSH3 and hMSH6. Mutations in these genes allow mistakes in tumor suppressor genes and oncogenes to accumulate which eventually leads to cancer. The founder of an HNPCC family in the Creighton University Hereditary Cancer Institute database was known to produce truncated hMLH1 protein, a product of one of the aforementioned mismatch repair genes. Lymphoblasts were isolated from ten members of this HNPCC family (six affected and four unaffected) and two persons from outside this family (both unaffected controls). RNA and DNA were purified from these lymphoblasts which had been transformed by the Epstein-Barr virus (EBV). The hypothesis was that a mutation in the hMLH1 gene perpetuated defects in its mRNA and functional protein. hMLH1 RNA transcripts were detected in reverse transcriptase polymerase chain reactions (RT-PCR) whereby total poly A(+) RNA was converted to a complementary DNA (cDNA), amplified using hMLH1 specific primers, purified and cycle sequenced. Likewise, DNA was employed as template for PCR amplification of hMLH1 exons; PCR products were then directly cycle sequenced. Affected family members were found to produce hMLH1 mRNA lacking exons 6 and 7 (and wild-type mRNA). A splicing mutation at 546--2 (two bases 5' to exon 7) was located in the genomic DNA samples from the six family members with the HNPCC phenotype. This mutation caused deletion of exon 7 from the mRNA. None of the four unaffected family members or the two unaffected persons outside of this family had the above defects in their hMLH1 mRNA and DNA.
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PMID:A hMLH1 genomic mutation and associated novel mRNA defects in a hereditary non-polyposis colorectal cancer family. 1205 1

MicroRNAs (miRNA), small noncoding RNAs, are potential diagnostic and prognostic markers, as well as therapeutic targets. miRNA profiles of colorectal carcinomas have not been studied extensively in the context of microsatellite instability (MSI) status. We therefore evaluated 55 paired colorectal adenocarcinomas (CRC) and non-neoplastic mucosa samples using a panel of 24 miRNAs selected by literature review and prior studies in our laboratory. Stem-loop reverse transcriptase quantitative (real-time) polymerase chain reaction assays were done on RNA extracted from formalin-fixed, paraffin-embedded tissue of resection specimens. When miRNA expression was compared with clinicopathologic features and MSI status, eleven miRNAs (miR-183, -31, -20, -25, -92, -93, -17, -135a, -203, -133b, and -223) were over-expressed in CRC relative to mucosa, and nine (miR-192, -215, -26b, -143, -145, -191, -196a, -16, and let-7a) were under-expressed in CRC. Relative expression of miR-92, -223, -155, -196a, -31, and -26b were significantly different among MSI subgroups, and miR-31 and miR-223 were overexpressed in CRC of patients with hereditary non-polyposis colorectal cancer syndrome (Lynch syndrome). Our findings indicate that miRNA expression in CRC is associated with MSI subgroups, including low MSI and HNPCC-associated cancers, and that miRNAs may have posttranscriptional gene regulatory roles in these MSI subgroups and possible effects on the clinicopathologic and biomarker characteristics.
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PMID:Association of microRNA expression with microsatellite instability status in colorectal adenocarcinoma. 2041 77

It has been reported that large genomic deletions in the MLH1 and MSH2 genes are a frequent cause of Lynch syndrome in certain populations. Here, a cohort has been screened and two new founder rearrangements have been found in the MSH2 gene. These mutations have been characterized by break point determination, haplotype analysis, and genotype-phenotype correlation. Mutations have been identified in the MLH1, MSH2, and MSH6 genes in 303 subjects from 160 suspected Lynch syndrome unrelated families. All subjects were tested using heteroduplex analysis by capillary array electrophoresis. Multiplex ligation-dependent probe amplification was used to detect rearrangements in mutation-negative index patients and confirmed by reverse transcriptase PCR. The break point of the deletions was further characterized by the array comparative genomic hybridization method. Immunohistochemical staining and microsatellite instability were studied in tumor samples. Hereditary nonpolyposis colorectal cancer-related phenotypes were evaluated. More than 16% (24 of 160) of the families had pathogenic mutations (8 MLH1, 15 MSH2, and 1 MSH6). Twelve of these families (50%) are carriers of a novel mutation. Seven of the 15 positive MSH2 families (47%) are carriers of a rearrangement. The exon 7 deletion and exon 4 to 8 deletion of MSH2 are new founder mutations. The segregation of a common haplotype, a similar phenotype, and anticipation effects were observed in these families. These findings will greatly simplify the diagnosis, counseling, and clinical care in suspected Lynch syndrome families and not just in specific geographic areas, so wide distribution may be explained by migration patterns.
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PMID:Characterization of new founder Alu-mediated rearrangements in MSH2 gene associated with a Lynch syndrome phenotype. 2197 78

Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch repair genes and leads to a high risk of colorectal and endometrial cancer. It was recently shown that constitutional 3' end deletions of EPCAM could cause Lynch syndrome in tissues with MSH2 deficiency. We aim to establish the spectrum of mutations in MSH2-associated Lynch syndrome cases and their clinical implications. Probands from 159 families suspected of having Lynch syndrome were enrolled in the study. Immunohistochemistry and microsatellite instability (MSI) analyses were used on the probands of all families. Eighteen cases with MSH2 loss were identified: eight had point mutations in MSH2. In 10 Lynch syndrome families without MSH2 mutations, EPCAM-MSH2genomic rearrangement screening was carried out with the use of multiplex ligation-dependent probe amplification and reverse transcriptase PCR. We report that large germline deletions, encompassing one or more exons of the MSH2 gene, cosegregate with the Lynch syndrome phenotype in 23% (8 of 35) of MSI families tested. A new combined deletion EPCAM-MSH2 was identified and characterized by break point analysis, encompassing from the 3' end region of EPCAM to the 5' initial sequences of the MSH2 (c.859-1860_MSH2:646-254del). EPCAM-MSH2 fusion transcript was isolated. The tumors of the carriers show high-level MSI and MSH2 protein loss. The clinical correlation provided evidence that the type of mutation and the extension of the deletions involving the MSH2 gene could have different implications in cancer predisposition. Thus, the identification of EPCAM-MSH2 rearrangements and their comprehensive characterization should be included in the routine mutation screening protocols for Lynch syndrome.
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PMID:Frequency of rearrangements in Lynch syndrome cases associated with MSH2: characterization of a new deletion involving both EPCAM and the 5' part of MSH2. 2197 78

Molecular pathogenesis and classification of colorectal carcinoma are based on the adenoma-carcinoma sequence in the Vogelstein model, serrated polyp pathway, and microsatellite instability. The genetic basis for hereditary nonpolyposis colorectal cancer is based on detection of genetic mutations. Genetic testing for Lynch syndrome includes microsatellite instability, methylator phenotyping, BRAF mutation, and molecular testing. Molecular makers include quantitative multigene reverse transcriptase-polymerase chain reaction assay and KRAS and BRAF mutation analysis. Potential biomarkers include one-step nucleic acid amplification and epigenetic inactivation of endothelin 2 and endothelin 3 in colon cancer. Molecular screening approaches in colorectal cancer using stool DNA are under investigation.
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PMID:Molecular diagnostics in colorectal carcinoma. 2426 89

Lynch syndrome is caused by inactivating mutations in the MLH1 gene, but genetic variants of unclear significance frequently preclude diagnosis. Functional testing can reveal variant-conferred defects in gene or protein function. Based on functional defect frequencies and clinical applicability of test systems, we developed a functional testing strategy aimed at efficiently detecting pathogenic defects in coding MLH1 variants. In this strategy, tests of repair activity and expression are prioritized over analyses of subcellular protein localization and messenger RNA (mRNA) formation. This strategy was used for four unclear coding MLH1 variants (p.Asp41His, p.Leu507Phe, p.Gln689Arg, p.Glu605del + p.Val716Met). Expression was analyzed using a transfection system, mismatch repair (MMR) activity by complementation in vitro, mRNA formation by reverse transcriptase-PCR in carrier lymphocyte mRNA, and subcellular localization with dye-labeled fusion constructs. All tests included clinically meaningful controls. The strategy enabled efficient identification of defects in two unclear variants: the p.Asp41His variant showed loss of MMR activity, whereas the compound variant p.Glu605del + p.Val716Met had a defect of expression. This expression defect was significantly stronger than the pathogenic expression reference variant analyzed in parallel, therefore the defect of the compound variant is also pathogenic. Interestingly, the expression defect was caused additively by both of the compound variants, at least one of which is non-pathogenic when occurring by itself. Tests were neutral for p.Leu507Phe and p.Gln689Arg, and the results were consistent with available clinical data. We finally discuss the improved sensitivity and efficiency of the applied strategy and its limitations in analyzing unclear coding MLH1 variants.
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PMID:Functional testing strategy for coding genetic variants of unclear significance in MLH1 in Lynch syndrome diagnosis. 2547 41

The molecular pathogenesis and classification of colorectal carcinoma are based on the traditional adenomaecarcinoma sequence, serrated polyp pathway, and microsatellite instability (MSI). The genetic basis for hereditary nonpolyposis colorectal cancer is the detection of mutations in the MLH1, MSH2, MSH6, PMS2, and EPCAM genes. Genetic testing for Lynch syndrome includes MSI testing, methylator phenotype testing, BRAF mutation testing, and molecular testing for germline mutations in MMR genes. Molecular makers with predictive and prognostic implications include quantitative multigene reverse transcriptase polymerase chain reaction assay and KRAS and BRAF mutation analysis. Mismatch repair-deficient tumors have higher rates of programmed death-ligand 1 expression. Cell-free DNA analysis in fluids are proving beneficial for diagnosis and prognosis in these disease states towards effective patient management.
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PMID:Molecular Diagnostics in Colorectal Carcinoma: Advances and Applications for 2018. 2977 33