Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have demonstrated the presence of microsatellite instability (MSI) in tumors from patients with hereditary nonpolyposis colorectal cancer and in a large number of sporadic tumors. To further characterize the type of alterations at these loci and their frequency of involvement in colon cancer, we studied DNA extracted from paraffin-embedded tissue from 508 patients using 11 microsatellites localized to chromosomes 5, 8, 15, 17, and 18. Overall, MSI at each locus varied in character and frequency and was observed with at least one marker in 191 cases (37.6%). Based on the number of markers displaying instability per tumor, three groups of patients were defined: those with <30% of the markers showing instability (MSI-L,, n = 109, 21.5%); those with > or = 30% (MSI-H, n = 82, 16.1%); and those showing no instability (MSS, n = 317, 62.4%). These groups were tested for correlations with a number of clinical and pathological parameters, including age, sex, stage, ploidy status, and site of tumor. Comparing across the three groups and verified by pair-wise comparisons, the MSI-H group was associated with tumor site (proximal colon, P = 0.001), sex (females, P = 0.005), stage (Dukes' B, P = 0.01), and ploidy status (diploid, P = 0.03). No significant differences were noted between the MSI-L and MSS group for any of the parameters tested. An additional 188 consecutive surgical colorectal cancer cases were examined for the presence of MSI and for the immunohistochemical expression of hMLH1 and hMSH2 proteins. Of this group, 129 (68.6%) were classified as MSS, 17 (9.0%) as MSI-L, and 42 (22.3%) as MSI-H. None of the MSS and none of the MSI-L tumors had altered expression of either hMLH1 or hMSH2. However, the majority of MSI-H (40 of 42, 95%) cases demonstrated absence of staining for these proteins. The most frequently altered protein was hMLH1, occurring in 95% of the tumors with altered expression. Cumulatively, these data suggest that the tumor phenotype MSI-H is distinct from tumor phenotypes MSI-L and MSS, with no apparent differences between MSI-L and MSS. Furthermore, altered hMLH1 protein expression appears to be responsible for the mutator phenotype in the vast majority of MSI-H tumors.
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PMID:Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. 956 88

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) is an autosomal dominantly inherited syndrome which confers an increased risk for colorectal cancer and endometrial cancer as well as other tumors. It is caused by germline DNA mismatch repair (MMR) gene mutations in five MMR genes, hMSH2, hMLH1, hPMS1, hPMS2 and hMSH6. Finding mutations in these high risk families means that you can offer presymptomatic carrier diagnosis and thereby identify individuals with a very high risk for cancer. These persons benefit from counseling and should be offered surveillance. We have used DGGE to screen members from 34 families for mutations in hMLH1 and hMSH2. Six mutations in five families were found, five of these mutations are new. Besides, three new polymorphisms were identified. The mutations were found in two of seven Amsterdam criteria HNPCC families and in three of four families with at least one case of early onset of CRC (before 35), suggesting there are appropriate families to be chosen for mutation screening in MMR genes.
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PMID:DGGE screening of mutations in mismatch repair genes (hMSH2 and hMLH1) in 34 Swedish families with colorectal cancer. 961 Oct 74

Inactivation of the genes involved in DNA mismatch repair is associated with microsatellite instability (MSI) in colorectal cancer. We report that hypermethylation of the 5' CpG island of hMLH1 is found in the majority of sporadic primary colorectal cancers with MSI, and that this methylation was often, but not invariably, associated with loss of hMLH1 protein expression. Such methylation also occurred, but was less common, in MSI- tumors, as well as in MSI+ tumors with known mutations of a mismatch repair gene (MMR). No hypermethylation of hMSH2 was found. Hypermethylation of colorectal cancer cell lines with MSI also was frequently observed, and in such cases, reversal of the methylation with 5-aza-2'-deoxycytidine not only resulted in reexpression of hMLH1 protein, but also in restoration of the MMR capacity in MMR-deficient cell lines. Our results suggest that microsatellite instability in sporadic colorectal cancer often results from epigenetic inactivation of hMLH1 in association with DNA methylation.
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PMID:Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. 961 5

We screened for germline mutations of mismatch repair genes, hMLH1 and hMSH2, in five Japanese families carrying hereditary nonpolyposis colorectal cancer (HNPCC) and in a patient with multiple primary cancers. Screening the entire coding regions of both genes using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis, we found two novel germline mutations in hMSH2. One was a 1-bp insertion in exon 12, detected in a patient who had undergone surgery six times for independent tumors (four primary colorectal carcinomas, a small intestinal carcinoma, and an endometrial cancer). The other, in a second patient, was a missense mutation from CTT to TTT at codon 390 in exon 7 that resulted in substitution of phenylalanine for leucine. This conservative alteration was not found in any of 50 normal controls, but we cannot exclude the possibility that it may represent a rare polymorphism rather than a factor in the disease.
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PMID:Novel germline mutations of hMSH2 in a patient with hereditary nonpolyposis colorectal cancer (HNPCC) and in a patient with six primary cancers. 962 22

Within the recent four years, there have been substantial advances in understanding the molecular pathogenesis of HNPCC. As one of the result of investigation, microsatellite instability has been observed in hereditary non-polyposis colorectal cancer (HNPCC) and other sporadic cancers. Moreover, there is strong supporting evidence that mismatch repair genes play a role in HNPCC. Here, we present our investigational results and discuss possible molecular mechanisms governing DNA mutation and genomic instability, leading to the development of neoplasm. We investigated replication error (RER) of 4 microsatellite markers (dinucleotide repeats) in 131 patients with colorectal cancer (10 met the criteria of HNPCC group B), using fluorescence-based DNA sequencer. We detected RER positivity (at more than two loci) in 12 of 131 patients (9.2%). PCR-SSCP and direct sequencing of the mismatch repair genes, hMSH2 and hMLH1, revealed that two patients in HNPCC group B had germline mutations of hMSH2. The fluorescence-based techniques, such as the present RER analysis do not require radioactive materials and specialized rooms, and can easily be performed in a clinical laboratory.
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PMID:[Analysis of genomic instability by fluorescence DNA sequencer]. 962 90

Muir-Torre syndrome (MTS) is an autosomal dominant disease defined by the coincidence of at least one sebaceous skin tumor and one internal malignancy. About half of MTS patients are affected by colorectal cancer. In a subgroup of MTS patients the disease has an underlying DNA mismatch-repair (MMR) defect and thus is allelic to hereditary nonpolyposis colorectal cancer (HNPCC). The purpose of this study was to examine to what extent germ-line mutations in DNA MMR genes are the underlying cause of the MTS phenotype. We ascertained 16 MTS patients with sebaceous skin tumors and colorectal cancer, and we examined their skin and visceral tumors for microsatellite instability. All the patients exhibited high genomic instability in at least one tumor. The search for germ-line mutations in the hMSH2 and hMLH1 genes in 13 of the MTS patients revealed truncating mutations in 9 (69%): eight mutations in the hMSH2 gene and one in the hMLH1 gene. This is the first systematic search for germ-line mutations in patients ascertained on the basis of sebaceous skin tumors. Our results indicate that (1) MTS patients exhibit significantly more mutations in the hMSH2 gene than in the hMLH1 gene; and (2) the subpopulation of MTS patients who are also affected by colorectal cancer, irrespective of family history and age at onset of tumors, may have a likelihood for an underlying DNA MMR defect similar to that for patients with a family history fulfilling the strict clinical criteria for HNPCC.
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PMID:Muir-Torre phenotype has a frequency of DNA mismatch-repair-gene mutations similar to that in hereditary nonpolyposis colorectal cancer families defined by the Amsterdam criteria. 963 24

All colorectal cancer results from the accumulation of critical genetic alterations; however, the mechanisms of acquiring these mutations appear to be different in hereditary nonpolyposis colon cancer (HNPCC) and sporadic tumors with microsatellite instability compared with sporadic tumors with no microsatellite instability. To further explore the possible mechanisms of cancer predisposition in HNPCC, we studied chromosome breakage and induction of aneuploidy in the lymphoblastoid cell lines of four patients who were heterozygous for mutations in either hMSH2 or hMLH1--two components of the DNA mismatch repair complex. Cells were cultured under different stress systems, including exposure to bleomycin, mitomycin C, bromodeoxyuridine-induced sister chromatid exchange, and a DNA alkylator, N-methyl-N'-nitro-N-nitrosoguanidine. No significant differences were detected in the levels of major or minor chromosome breakage or aneuploidy compared with controls. These results suggest that a single "hit" to a DNA mismatch repair gene does not confer appreciable susceptibility to structural or numerical chromosomal alterations, which is consistent with previous observations that HNPCC-related cancers are more likely to be near diploid than are sporadic colon cancers.
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PMID:Search for chromosome instability in lymphocytes with germ-line mutations in DNA mismatch repair genes. 964 58

The molecular genetics of the hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) is reviewed. Recently, four genes (hMSH2, hMLH1, hPMS1, hPMS2) whose mutations are related to HNPCC were discovered. The products of these genes are homologues of the bacterial mismatch repair (MMR) system proteins MutS and MutL. Dysfunction of MMR system both in bacterial and human cells leads to the microsatellite instability (MI) in repetitive sequences of DNA. These sequences are also present in some tumor suppressor genes (e.g. TGF-beta RII or BAX). Therefore, the MI probably leads to the impairment of the cell cycle regulation and a carcinoma can develop from the clone of such cells with nonregulated growth.
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PMID:[Review of the molecular genetics of the Lynch syndrome]. 965 Apr 15

Recent studies have demonstrated the presence of microsatellite instability (MSI) in tumors from patients with hereditary nonpolyposis colon cancer and in a subset of patients with sporadic colorectal cancer (CRC). In sporadic CRC, three tumor phenotypes have been defined: microsatellite stable (MSS), low-frequency MSI, and high-frequency MSI (MSI-H). Although defective mismatch repair, consisting primarily of alterations in hMSH2 and hMLH1, is believed to be responsible for the MSI phenotype in the majority of patients with hereditary nonpolyposis colon cancer, the genetic defect responsible for this phenotype in sporadic CRC has yet to be clearly delineated. Somatic or germ-line alterations in these two genes have been identified in only a minority of these cases. Analysis of the protein expression patterns of hMSH2 and hMLH1 in unselected CRC, however, suggests that alterations in hMLH1 may account for a majority of the MSI-H cases. In an effort to explore the underlying molecular basis for these findings, we have examined the methylation status of the presumptive hMLHI promoter region in 31 tumors that vary in regard to their MSI status (MSI-H or MSS), their hMLH1 protein expression (MLH- or MLH+), and their gene mutation (Mut+ or Mut-) status. Hypermethylation of the hMLH1 promoter occurred in all 13 MSI-H/ MLH- tumors that did not have a detectable mutation within the hMLH1 gene. Of those MSI-H tumors containing germ-line or somatic alterations in hMLH1 (n = 7, including 3 frameshift, 1 nonsense, 2 missense mutations, and 1 tumor containing multiple mutations: missense, splice-site alteration, and a frameshift), four had a normal methylation pattern, whereas three others demonstrated hypermethylation of the hMLH1 promoter region. Two of these cases had a missense alteration, the other a frameshift alteration. The single MSI-H/Mut+ tumor that had normal hMLH1 and hMSH2 expression, as well as 9 of the 10 MSS cases, lacked methylation of the hMLH1 promoter. Hypermethylation of the hMSH2 promoter was not observed for any of the cases. These results suggest that hypermethylation of the hMLH1 promoter may be the principal mechanism of gene inactivation in sporadic CRC characterized by widespread MSI.
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PMID:Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. 969 80


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