Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of DNA mismatch repair occurs in many types of tumors. The effect of the loss of DNA mismatch repair activity on sensitivity to cisplatin and a panel of analogues was tested using two pairs of cell lines proficient or deficient in this function. HCT116+ch2, a human colon cancer cell line deficient in hMLH1, was 2.1-fold resistant to cisplatin and 1.3-fold resistant to carboplatin when compared to a subline complemented with chromosome 3 expressing a wild-type copy of hMLH1. Likewise, the human endometrial cancer cell line HEC59, which is deficient in hMSH2, was 1.8-fold resistant to cisplatin and 1.5-fold resistant to carboplatin when compared to a subline complemented with chromosome 2 with a wild-type hMSH2. In contrast to cisplatin and carboplatin, which form the same types of adducts in DNA, there was no difference in sensitivity between the DNA mismatch repair-proficient and -deficient cell lines for oxaliplatin, tetraplatin, transplatin, JM335, or JM216. The formation of protein-DNA complexes that contained hMSH2 and hMLH1 was documented by mobility shift assay when nuclear extracts were incubated with DNA platinated with cisplatin but not with oxaliplatin. These results demonstrate a correlation between failure of the DNA mismatch repair proteins to recognize the platinum adduct and low-level resistance, suggesting a role for the DNA mismatch repair system in generating signals that contribute to the generation of apoptotic activity. They also identify the use of drugs whose adducts are not recognized as a strategy for circumventing resistance due to loss of DNA mismatch repair.
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PMID:The role of DNA mismatch repair in platinum drug resistance. 889 38

Hereditary non-polyposis colorectal cancer (HNPCC) is a syndrome of inherited bowel and other cancers that has been said to account for up to 15% of all colorectal carcinomas (CRCs). HNPCC can now be diagnosed at the molecular level by detecting germline mutations in genes involved in mismatch repair. A current problem is to determine the prevalence of HNPCC mutations in colon cancer patients with limited or no family history, especially in cases of early onset. We have identified 50 cases of non-polyposis colorectal cancer without a family history of CRC or any other HNPCC cancer, who presented under the age of 45 years. Germline HNPCC variants (at the hMSH2 or hMLH1 loci) were detected in a small minority of cases (6%). The variants that we have found may be new or low penetrance mutations, or even polymorphisms. It remains possible that some of our sample have an inherited predisposition to CRC that is not caused by HNPCC mutations or by known polyposis syndromes. Our data suggest that most HNPCC mutations occur in families and have high or moderate penetrance. New or low penetrance HNPCC mutations probably do not contribute significantly to the risk of colorectal cancer in the general population and probably account for much fewer than 15% of all CRCs. Our results question whether mass population genetic screening programmes are worthwhile for diseases such as HNPCC using current technology.
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PMID:Germline HNPCC gene variants have little influence on the risk for sporadic colorectal cancer. 903 48

hMLH1 and hPMS2 are part of the DNA mismatch repair complex. Mutations in these genes have been linked to hereditary non-polyposis colon cancer; they also occur in a variety of sporadic cancers. Western blot analysis and immunohistochemistry demonstrated that hMLH1 and hPMS2 are widely expressed nuclear proteins with a distribution pattern very similar to that previously described for hMSH2. These observations showing similar localization of hMLH1 and hPMS2 with hMSH2 are consistent with the biochemical function of these proteins in DNA mismatch repair.
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PMID:Expression of the DNA mismatch repair proteins hMLH1 and hPMS2 in normal human tissues. 932 48

Hereditary non-polyposis colon cancer (HNPCC) is a common hereditary disease characterized by a predisposition to an early onset of colorectal cancer. The majority of the HNPCC families carry germline mutations of either hMSH2 or hMLH1 genes, whereas germline mutations of hPMS1 and hPMS2 genes have rarely been observed. Almost all of the germline mutations reported so far concern typical HNPCC families. However, there are families that display aggregations of colon cancer even though they do not fulfil all HNPCC criteria (incomplete HNPCC families) as well as sporadic cases of early onset colon cancers that could be related to germline mutations of these genes. Therefore, we screened germline mutations of hMSH2 and hMLH1 genes in 3 groups of patients from France and Turkey: typical HNPCC (n = 3), incomplete HNPCC (n = 9) and young patients without apparent familial history (n = 7). By in vitro synthesis of protein assay, heteroduplex analysis and direct genomic sequencing, we identified 1 family with hMSH2 mutation and 5 families with hMLH1 mutations. Two of the 3 HNPCC families (66%) displayed hMLH1 germline mutations. Interestingly, 4 of 9 families with incomplete HNPCC (44%) also displayed mutations of hMSH2 or hMLH1 genes. In contrast, no germline mutation of these genes was found in 7 young patients. Our results show that germline mutations of hMSH2 and hMLH1 genes contribute to a significant fraction of familial predisposition to colon cancer cases that do not fulfil all diagnostic criteria of HNPCC.
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PMID:Germline hMSH2 and hMLH1 gene mutations in incomplete HNPCC families. 939 61

Colorectal cancer is a significant cause of morbidity and mortality in Western populations. This cancer develops as a result of the pathologic transformation of normal colonic epithelium to an adenomatous polyp and ultimately an invasive cancer. The multistep progression requires years and possibly decades and is accompanied by a number of recently characterized genetic alterations. Mutations in two classes of genes, tumor-suppressor genes and proto-oncogenes, are thought to impart a proliferative advantage to cells and contribute to development of the malignant phenotype. Inactivating mutations of both copies (alleles) of the adenomatous polyposis coli (APC) gene--a tumor-suppressor gene on chromosome 5q--mark one of the earliest events in colorectal carcinogenesis. Germline mutation of the APC gene and subsequent somatic mutation of the second APC allele cause the inherited familial adenomatous polyposis syndrome. This syndrome is characterized by the presence of hundreds to thousands of colonic adenomatous polyps. If these polyps are left untreated, colorectal cancer develops. Mutation leading to dysregulation of the K-ras protooncogene is also thought to be an early event in colon cancer formation. Conversely, loss of heterozygosity on the long arm of chromosome 18 (18q) occurs later in the sequence of development from adenoma to carcinoma, and this mutation may predict poor prognosis. Loss of the 18q region is thought to contribute to inactivation of the DCC tumor-suppressor gene. More recent evidence suggests that other tumor-suppressor genes--DPC4 and MADR2 of the transforming growth factor beta (TGF-beta) pathway--also may be inactivated by allelic loss on chromosome 18q. In addition, mutation of the tumor-suppressor gene p53 on chromosome 17p appears to be a late phenomenon in colorectal carcinogenesis. This mutation may allow the growing tumor with multiple genetic alterations to evade cell cycle arrest and apoptosis. Neoplastic progression is probably accompanied by additional, undiscovered genetic events, which are indicated by allelic loss on chromosomes 1q, 4p, 6p, 8p, 9q, and 22q in 25% to 50% of colorectal cancers. Recently, a third class of genes, DNA repair genes, has been implicated in tumorigenesis of colorectal cancer. Study findings suggest that DNA mismatch repair deficiency, due to germline mutation of the hMSH2, hMLH1, hPMS1, or hPMS2 genes, contributes to development of hereditary nonpolyposis colorectal cancer. The majority of tumors in patients with this disease and 10% to 15% of sporadic colon cancers display microsatellite instability, also know as the replication error positive (RER+) phenotype. This molecular marker of DNA mismatch repair deficiency may predict improved patient survival. Mismatch repair deficiency is thought to lead to mutation and inactivation of the genes for type II TGF-beta receptor and insulin-like growth-factor II receptor. Individuals from families at high risk for colorectal cancer (hereditary nonpolyposis colorectal cancer or familial adenomatous polyposis) should be offered genetic counseling, predictive molecular testing, and when indicated, endoscopic surveillance at appropriate intervals. Recent studies have examined colorectal carcinogenesis in the light of other genetic processes. Telomerase activity is present in almost all cancers, including colorectal cancer, but rarely in benign lesions such as adenomatous polyps or normal tissues. Furthermore, genetic alterations that allow transformed colorectal epithelial cells to escape cell cycle arrest or apoptosis also have been recognized. In addition, hypomethylation or hypermethylation of DNA sequences may alter gene expression without nucleic acid mutation.
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PMID:Molecular biology of colorectal cancer. 943 4

Abnormalities in at least 1 of 5 mismatch repair (MMR) genes (hMSH2, hMLH1, hPMS1, hPMS2 and GTBP/hMSH6) are found in hereditary nonpolyposis colon cancer and sporadic colon cancers. We used a single-reaction multiplex reverse transcription (RT)-polymerase chain reaction (PCR), with the beta-actin gene as an internal control, to simultaneously evaluate expression of these 5 known human MMR genes in normal and tumor cell lines with known or uncharacterized mutations in MMR genes. The relative quantitation of the transcripts is demonstrated by controlling the number of PCR cycles and titrating cDNA with a dose-curve. The 13 normal cell lines tested were derived from normal lymphocytes, skin, thymus, breast, lung, colon, liver and kidney. The 26 cancer cell lines were derived from melanoma and cancers of the brain, breast, lung, colon, pancreas and prostate. All 5 MMR genes were ubiquitously expressed in all normal cell lines tested, suggesting their housekeeping roles. Aberrant MMR gene expression was only observed in the colon cancer cell lines. Two previously uncharacterized colon cancer cell lines did not express hMLH1. These data suggest that this nonradioactive multiplex RT-PCR assay for MMR gene expression may be useful for fast screening for genetic alterations that may affect gene expression and so may aid molecular analysis of MMR-related colon cancer.
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PMID:Expression of five selected human mismatch repair genes simultaneously detected in normal and cancer cell lines by a nonradioactive multiplex reverse transcription-polymerase chain reaction. 949 49

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

Oxaliplatin, the first available diaminocyclohexane platinum, has clinical activity in colorectal and ovarian cancers. Its mechanism of action is thought to be similar to that of cisplatin, its main mechanism being the intrastrand DNA adduct between two adjacent guanins or two adjacent guanine and adenine adducts. Ongoing molecular pharmacological studies of the mechanism of action of cisplatin suggest that platinated adducts are recognized by proteins of the mismatch repair system, including the products of the hMLH1 and hMSH2 genes. DNA mismatch repair defects occur in a wide variety of sporadic human cancers, are the main genetic factor in hereditary non-polyposis colon cancer and a frequent de novo or acquired phenomenon in ovarian cancer and other solid tumours. Moreover, they have recently been reported to be a cause of resistance to cisplatin but not to oxaliplatin, as diaminocyclohexane platinum adducts do not appear to be recognized by the mismatch repair complex. These findings explain the oxaliplatin activity in some cisplatin-resistant tumours. In addition, the good safety profile of oxaliplatin makes it a drug of choice for combination therapy, and it has been shown to be synergistic with other cytotoxic agents, including 5-fluorouracil, cisplatin, carboplatin, topotecan, gemcitabine and CPT-11. The results of several ongoing trials are awaited, but available data demonstrate that oxaliplatin is highly effective in the treatment of advanced colorectal and ovarian cancers. Promising early results suggest that it is also efficacious in non-Hodgkin's lymphoma, breast and non-small-cell lung cancers. As a result of its mechanism of action, its favourable safety profile and the differential profile of its antitumoral activity, the full potential of oxaliplatin as an active, versatile antitumoral agent is yet to be fully explored.
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PMID:Ongoing and unsaid on oxaliplatin: the hope. 964 13

Germ-line mutations in DNA mismatch-repair genes impart a markedly elevated cancer risk, often presenting as autosomal dominant hereditary nonpolyposis colorectal cancer (HNPCC). However, there are no pathognomonic features of HNPCC, not all gene carriers have a family history of the disease, and families fulfilling the Amsterdam criteria are relatively uncommon. Genetic testing of probands with early-onset colorectal cancer, irrespective of family history, is one approach that would allow predictive genetic testing of at-risk relatives. We cloned and sequenced hMSH2 and hMLH1 introns, to optimize genomic sequencing. We then systematically analyzed the entire hMSH2 and hMLH1 genes, by genomic sequencing and in vitro synthesized-protein-truncation assay (IVSP), in 50 colorectal cancer patients <30 years of age at diagnosis. To determine polymorphic variants, 26 anonymous donors also were sequenced. All subjects analyzed had at least 1 of 37 different polymorphic or pathogenic variants. IVSP complemented genomic sequencing, by detection of mutations not identified by genomic analysis. Fourteen cancer patients (28%) had pathogenic mutations, and a number of other variants also may have had a pathogenic significance that remains to be elucidated. Tumor replication-error status was useful in targeting sequencing efforts for this cohort of young patients: sensitivity was 86%, specificity 73%, and positive and negative predictive values 63% and 90%, respectively. These data indicate that an appreciable proportion of young colon cancer probands carry a germ-line mutation in a DNA mismatch-repair gene.
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PMID:Systematic analysis of hMSH2 and hMLH1 in young colon cancer patients and controls. 971 27


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