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)

Hereditary non-polyposis colorectal cancer (HNPCC) is the most common genetic susceptibility syndrome for colorectal cancer. HNPCC is most frequently caused by germline mutations in the DNA mismatch repair (MMR) genes MSH2 and MLH1. Recently, mutations in another MMR gene, MSH6 (also known as GTBP), have also been shown to result in HNPCC. Preliminary data indicate that the phenotype related to MSH6 mutations may differ from the classical HNPCC caused by defects in MSH2 and MLH1. Here, we describe an extended Dutch HNPCC family not fulfilling the Amsterdam criteria II and resulting from a MSH6 mutation. Overall, the penetrance of colorectal cancer appears to be significantly decreased (p<0.001) among the MSH6 mutation carriers in this family when compared with MSH2 and MLH1 carriers (32% by the age of 80 v >80%). Endometrial cancer is a frequent manifestation among female carriers (six out of 13 malignant tumours). Transitional cell carcinoma of the urinary tract is also relatively common in both male and female carriers (10% of the carriers). Moreover, the mean age of onset of both colorectal cancer (MSH6 v MSH2/MLH1 = 55 years v 44/41 years) and endometrial carcinomas (MSH6 v MSH2/MLH1 = 55 years v 49/48 years) is delayed. As previously reported, we confirm that the pattern of microsatellite instability, in combination with immunohistochemical analysis, can predict the presence of a MSH6 germline defect. The detailed characterisation of the clinical phenotype of this kindred contributes to the establishment of genotype-phenotype correlations in HNPCC owing to mutations in specific mismatch repair genes.
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PMID:Atypical HNPCC owing to MSH6 germline mutations: analysis of a large Dutch pedigree. 1133 68

Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is the most common autosomal dominant condition associated with early-onset colorectal cancer and the occurrence of cancer at other anatomical sites, i.e. endometrium, stomach, small intestine, urinary tract and ovaries, at an early age. Germline mutations in one of five DNA mismatch repair genes: MSH2, MLH1, PMS1, PMS2, and MSH6, predispose to HNPCC. Tumours of HNPCC patients display a high level of genomic instability, usually observed as changes in repeat numbers of simple repetitive sequences (microsatellite instability), which is a reflection of the malfunction of the DNA mismatch repair machinery.
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PMID:[From gene to disease; from DNA 'mismatch' repair genes to hereditary non-polyposis colorectal carcinoma]. 1134 16

Loss of mismatch repair (MMR) function leads to the accumulation of errors that normally occur during DNA replication, resulting in genetic instability. Germ-line mutations of MMR genes in the patients with hereditary nonpolyposis colorectal cancer lead to inactivation of MMR protein functions, and the defects of MMR are well correlated to the high rate of microsatellite instability in their tumors. Previous studies (T. Uchida, et al. Oncogene, 10: 1019-1022, 1995; S. Egawa, et al. Cancer RES:, 55: 2418-2421, 1995; J. M. Cunningham, et al. Cancer RES:, 56: 4475-4482, 1996; X. Gao, et al. Oncogene, 9: 2999-3003, 1994; H. Rohrbach, et al. Prostate, 40: 20-27, 1999) have shown that genetic instability (chromosomal and microsatellite instability) is detectable in human prostate cancer. To elucidate the role of MMR genes in the tumorigenesis of prostate cancer, we evaluated the expression of these genes in human cancer cell lines and in tumor specimens. Using Western blot analysis, we detected loss among MSH2, MLH1, PMS2, and PMS1 proteins in DU145, LNCaP, p69SV40T, M2182, and M12 cells. In addition, genomic instability in the prostate cell lines including DU145, PC3, LNCaP, p67SV40T, M2182, and M12 was detected by a microsatellite mutation assay. Significantly, immunohistochemical analysis of prostatic tissue revealed the reduction or absence of MMR protein expression in the epithelium of prostate tumor foci compared with normal adjacent prostate tissue. In contrast to hereditary nonpolyposis colorectal cancer, characterized by defects predominantly in MLH1 and MSH2, the samples we examined showed more tumor foci with loss of PMS1 and PMS2. PMS1, which is only expressed in the basal cells in normal glands, is conspicuously absent in most prostate cancer. From these results, we conclude that there are defects of MMR genes in human prostate cancer.
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PMID:Defects of DNA mismatch repair in human prostate cancer. 1135 34

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations of genes encoding for proteins of the mismatch repair (MMR) machinery. The majority of mutations occur in the MLH1 and MSH2 genes, and consist of splice-site, frameshift and nonsense changes, leading to loss of protein function. In this study, we screened 7 HNPCC families for MLH1/MSH2 mutations. Sequence changes were identified in 5 families. Four alterations were novel 1- or 2-bp deletions or insertions causing a frameshift and appearance of premature stop codons (MLH1: c.597-598delGA, c.1520-1521insT; MSH2: c.1444delA, c.119delG). The four small insertions/ deletions were located within stretches of simple repeated sequences. By reviewing the HNPCC mutation database, we found that the majority of 1-2 bp frameshift mutations similarly affects simple repetitive stretches, pointing to DNA polymerase slippage during replication as the most likely source of such errors. We also evaluated microsatellite instability (MSI) in a breast carcinoma (BC) from an MLH1 mutation carrier. While a colon cancer from the same individual showed MSI, the BC specimen was MSI-negative, indicating that development of the latter tumor was unrelated to MMR impairment, despite presence of a constitutional MLH1 mutation. Hum Mutat 17:521, 2001.
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PMID:Four novel MSH2 and MLH1 frameshift mutations and occurrence of a breast cancer phenocopy in hereditary nonpolyposis colorectal cancer. 1138 12

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant cancer predisposition syndrome caused by germ-line mutations in DNA mismatch repair genes. It is relevant to identify HNPCC patients because colonoscopic screening of individuals with HNPCC mutations reduces cancer morbidity and mortality. Microsatellite instability (MSI) is characteristic of HNPCC tumors. A panel of five markers (BAT25, BAT26, D2S123, D5S346, and D17S250, the so-called Bethesda markers) has been proposed for screening for MSI. To test a hypothesis that the use of BAT26 alone is feasible in screening for MLH1/MSH2 mutation-positive HNPCC patients, we compared the MSI results of 494 colorectal cancer patients obtained using BAT26 with results obtained using the Bethesda markers. BAT26 was able to identify all 27 mutation-positive individuals in this series. The marker failed to identify 2 high MSI tumors and 20 low MSI tumors, all of which expressed MLH1, MSH2, and MSH6 when scrutinized by immunohistochemistry.
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PMID:Microsatellite marker analysis in screening for hereditary nonpolyposis colorectal cancer (HNPCC). 1138 88

DNA mismatch repair (MMR) is an efficient system for the detection and repair of mismatched and unpaired bases in DNA. Deficiencies in MMR are commonly found in both hereditary and sporadic colorectal cancers, as well as in cancers of other tissues. Because fluorinated thymidine analogues (which through their actions might generate lesions recognizable by MMR) are widely used in the treatment of colorectal cancer, we investigated the role of MMR in cellular responses to 5-fluorouracil and 5-fluoro-2'-deoxyuridine (FdUrd). Human MLH1(-) and MMR-deficient HCT116 colon cancer cells were 18-fold more resistant to 7.5 microM 5-fluorouracil (continuous treatment) and 17-fold more resistant to 7.5 microM FdUrd in clonogenic survival assays compared with genetically matched, MLH1(+) and MMR-proficient HCT116 3-6 cells. Likewise, murine MLH1(-) and MMR-deficient CT-5 cells were 3-fold more resistant to a 2-h pulse of 10 microM FdUrd than their MLH1(+) and MMR-proficient ME-10 counterparts. Decreased cytotoxicity in MMR-deficient cells after treatment with various methylating agents and other base analogues has been well reported and is believed to reflect a tolerance to DNA damage. Synchronized HCT116 3-6 cells treated with a low dose of FdUrd had a 2-fold greater G(2) cell cycle arrest compared with MMR-deficient HCT116 cells, and asynchronous ME-10 cells demonstrated a 4-fold greater G(2) arrest after FdUrd treatment compared with CT-5 cells. Enhanced G(2) arrest in MMR-proficient cells in response to other agents has been reported and is believed to allow time for DNA repair. G(2) cell cycle arrest as determined by propidium iodide staining was not a result of mitotic arrest, but rather a true G(2) arrest, as indicated by elevated cyclin B1 levels and a lack of staining with mitotic protein monoclonal antibody 2. Additionally, p53 and GADD45 levels were induced in FdUrd-treated HCT116 3-6 cells. DNA double-strand break (DSB) formation was 2-fold higher in MMR-proficient HCT116 3-6 cells after FdUrd treatment, as determined by pulsed-field gel electrophoresis. The formation of DSBs was not the result of enhanced apoptosis in MMR-proficient cells. FdUrd-mediated cytotoxicity was caused by DNA-directed and not RNA-directed effects, because administration of excess thymidine (and not uridine) prevented cytotoxicity, cell cycle arrest, and DSB formation. hMLH1-dependent responses to fluoropyrimidine treatment, which may involve the action of p53 and the formation of DSBs, clearly have clinical relevance for the use of this class of drugs in the treatment of tumors with MMR deficiencies.
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PMID:Role of the hMLH1 DNA mismatch repair protein in fluoropyrimidine-mediated cell death and cell cycle responses. 1143 59

Nonrandom, widespread promoter methylation of tumor suppressor genes is a common mechanism of gene inactivation during tumorigenesis. We examined the methylation status of two distinct regions of the MLH1 promoter (proximal and distal to the transcription start site) and the MLH1 gene expression by methylation-specific PCR and immunohistochemistry. A total of 72 colorectal tumors, both with (n = 51, 22 affected by hereditary nonpolyposis colorectal cancer, HNPCC, defined according to the international clinical criteria and 29 sporadic cases) and without microsatellite instability (MSI) (n = 21) were studied. Methylation was present in at least one of the two promoter regions in 86% of the sporadic MSI cases, in 33% of the cases lacking MSI, and in 23% of the HNPCC tumors. In the HNPCC cases with a known MLH1 mutation (n = 10) none of the two promoter regions was methylated. Hypermethylation in both MLH1 promoter regions was seen in 45% of the MSI sporadic cases vs. 5% of the MSI-negative cases and 0% of the HNPCC cases. The overall concordance between the two promoter regions regarding methylation status was good (P = 0.009), but no significant correlation between methylation and suppression of the MLH1 immunohistochemical expression was found. Our data confirm that mutation and hypermethylation are mutually exclusive mechanisms in inducing mismatch repair deficiency and support the hypothesis of methylation as a process evenly distributed along the different regions of the promoter.
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PMID:Methylation pattern of different regions of the MLH1 promoter and silencing of gene expression in hereditary and sporadic colorectal cancer. 1143 26

Hereditary nonpolyposis colorectal cancer is associated with inherited defects in DNA mismatch repair. Clinical variation even in cases with identical predisposing mutations suggests the existence of other factors contributing to the phenotype. We addressed the modifying role of the common A/G polymorphism in exon 4 and the alternatively spliced transcripts a and b of the CCND1 gene encoding cyclin D1 in a series of 146 affected carriers of 10 MLH1 and 3 MSH2 mutations. No correlation was observed between a particular allele (A versus G) and age at onset. However, the presence of the variant transcript b in blood/normal mucosa, by multiplex reverse transcription-PCR, was associated with a significantly lower age at onset of colon cancer as compared with individuals with transcript a only (35 versus 46 years; P = 0.02). Whereas our data do not support a modifying role of A versus G allele of CCND1, the results do suggest that the relative abundance of a and b transcripts may modify the age at onset of colon cancer in hereditary nonpolyposis colorectal cancer.
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PMID:CYCLIN D1 as a genetic modifier in hereditary nonpolyposis colorectal cancer. 1150 50

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant inherited disease caused by defects in the process of DNA mismatch repair (MMR), and mutations in the hMLH1 or hMSH2 genes are responsible for the majority of HNPCC. In addition to clear loss-of-function mutations conferred by nonsense or frameshift alterations in the coding sequence or by splice variants, genetic screening has revealed a large number of missense codons with less obvious functional consequences. The ability to discriminate between a loss-of-function mutation and a silent polymorphism is important for genetic testing for inherited diseases like HNPCC where the opportunity exists for early diagnosis and preventive intervention. In this study, quantitative in vivo DNA MMR assays in the yeast Saccharomyces cerevisiae were performed to determine the functional significance of amino acid replacements observed in the human population. Missense codons previously observed in human genes were introduced at the homologous residue in the yeast MLH1 or MSH2 genes. This study also demonstrated feasibility of constructing genes that encode functional hybrid human-yeast MLH1 proteins. Three classes of missense codons were found: (i) complete loss of function, i.e. mutations; (ii) variants indistinguishable from wild-type protein, i.e. silent polymorphisms; and (iii) functional variants which support MMR at reduced efficiency, i.e. efficiency polymorphisms. There was a good correlation between the functional results in yeast and available human clinical data regarding penetrance of the missense codon. The results reported here raise the intriguing possibility that differences in the efficiency of DNA MMR exist between individuals in the human population due to common polymorphisms.
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PMID:Functional analysis of human MLH1 and MSH2 missense variants and hybrid human-yeast MLH1 proteins in Saccharomyces cerevisiae. 1155 25

An importance-sampling method is presented that allows the simulation of the history of a selected allele in a population of variable size. A sample path describing the number of copies of an allele that arose as a single mutant is generated by simulating backwards from the current frequency until the allele is lost. The mathematical expectation of a quantity or statistic is then estimated by taking averages over replicate simulations, weighting each replicate by the ratio of its probabilities under the Markov chains for the forward and backwards processes. This method was used to find the average age of a selected allele in an exponentially growing population. In terms of the effect on average allele age, selection in favour of an allele is not equivalent to exponential growth. To generate gene genealogies of a sample of copies of a selected allele, the neutral coalescent model is simulated for the subpopulation containing only the selected allele. From the resulting intra-allelic genealogy, it is possible to calculate the likelihood of the selection intensity as a function of the observed level of variability at marker loci closely linked to the selected allele. This method was used to estimate the intensity of selection affecting the delta 32 allele at the CCR5 locus in Europeans and a mutant at the MLH1 locus associated with colorectal cancer in the Finnish population.
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PMID:Simulating genealogies of selected alleles in a population of variable size. 1155 37


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