UMLS:C0009402 - FACTA Search

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Query: UMLS:C0009402 (colorectal cancer)
53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Somatic mutations within a mononucleotide repeat sequence present in the hMSH6 and hMSH3 coding regions have been frequently observed in various human cancer tissues and cell lines showing genomic instability. However, relatively few germline mutations of the repeat sequence have been identified. Two germline mutations in the hMSH6 region have been reported in hereditary nonpolyposis colorectal cancer (HNPCC); however, no germline mutations in the hMSH3 gene have been reported yet. To investigate genetic alterations within an 8 bp polycytosine repeat of the hMSH6 gene and an 8-bp polyadenine repeat of the hMSH3 gene, we amplified the mononucleotide repeat sequences of 35 HNPCC patients, 44 patients suspected of having HNPCC who did not fulfill the criteria of the International Collaborative Group on HNPCC, and 45 patients with sporadic early-onset colorectal cancer who developed colorectal cancer before the age of 40 years without any family history of colorectal cancer. Genetic alteration of the repeat sequence of the hMSH3 gene was not observed, whereas germline frame-shift mutations (one C insertion) in the hMSH6 gene were found in two of the 44 suspected HNPCC patient in whom germline mutations of hMSH2 or hMLH1 had not been detected. An identical frameshift mutation was also observed in another affected member of a suspected HNPCC family. These results suggest that the mutation of hMSH6 is responsible for tumorigenesis in minor groups of suspected HNPCC patients.
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PMID:Germline mutations in a polycytosine repeat of the hMSH6 gene in Korean hereditary nonpolyposis colorectal cancer. 992 71

Germline mutations in two human mismatch repair (MMR) genes, hMSH2 and hMLH1, appear to account for approximately 70% of the common cancer susceptibility syndrome hereditary nonpolyposis colorectal cancer (HNPCC). Although the hMLH1 protein has been found to copurify with another MMR protein hPMS2 as a heterodimer, their function in MMR is unknown. In this study, we have identified the physical interaction regions of both hMLH1 with hPMS2. We then examined the effects of hMLH1 missense alterations found in HNPCC kindreds for their interaction with hPMS2. Four of these missense alterations (L574P, K616Delta, R659P, and A681T) displayed >95% reduction in binding to hPMS2. Two additional missense alterations (K618A and K618T) displayed a >85% reduction in binding to hPMS2, whereas three missense alterations (S44F, V506A, and E578G) displayed 25-65% reduction in binding to hPMS2. Interestingly, two HNPCC missense alterations (Q542L and L582V) contained within the consensus interaction region displayed no effect on interaction with hPMS2, suggesting that they may affect other functions of hMLH1. These data confirm that functional deficiencies in the interaction of hMLH1 with hPMS2 are associated with HNPCC as well as suggest that other unknown functional alteration of the human MutL homologues may lead to tumorigenesis in HNPCC kindreds.
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PMID:The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer. 1003 23

The hMLH1 gene encodes a protein that is involved in the DNA mismatch repair system. The coding region of the hMLH1 gene has been known to be mutated in a subset of patients with hereditary nonpolyposis colorectal cancer (HNPCC). Our current research characterized the promoter region of the hMLH1 gene and searched for mutations correlating to HNPCC. Utilizing the oligo-capping method, major transcription start sites of the hMLH1 gene were mapped at two locations. The core promoter region of about 180 bp was determined by the luciferase assay of serial deletion mutants. Although we did not find any pathogenic mutation in the hMLH1 promoter region by PCR-SSCP, we found a single-nucleotide polymorphism at position -93 nt from the adenine residue of the start codon. By PCR-RFLP analysis with Pvu II for this polymorphism, we detected LOH in four tumors from three patients. An easy detection of this polymorphism with PCR-RFLP and high incidence ( approximately 50%) of informative cases make this polymorphism a suitable marker for the detection of hMLH1 allelic losses.
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PMID:A core promoter and a frequent single-nucleotide polymorphism of the mismatch repair gene hMLH1. 1008 Sep 25

The human PMS2 gene encodes one of the bacterial mutL homologs that is associated with hereditary nonpolyposis colorectal cancer (HNPCC). One of the interesting features of the hPMS2 gene is that it is part of a multiple gene family which is localized on chromosome bands 7p22, 7p12-p13, 7q11, and 7q22. Here we report four newly identified hPMS2-like (PMS2L) genes. All four novel members of the PMS2L gene family encode relatively short polypeptides composed of the amino-terminal portion of hPMS2 and are expressed ubiquitously except in the heart. To clarify whether the PMS2L polypeptides contribute to the DNA mismatch repair (MMR) pathway through an interaction with hMLH1, we have performed a yeast two-hybrid assay and an immunoprecipitation study using an hPMS2 mutant cell line, HEC-1-A. Our results clearly indicate that hMLH1 does not interact with two representative PMS2Ls, whereas the carboxyl-terminal portion of hPMS2, not the amino-terminal portion, does interact with hMLH1. Thus, PMS2Ls are not likely to participate in the MMR pathway through association with hMLH1; they must play some other roles in the living cells.
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PMID:The human PMS2L proteins do not interact with hMLH1, a major DNA mismatch repair protein. 1010 Dec 97

Hereditary non-polyposis colorectal cancer (HNPCC) is a dominantly inherited cancer syndrome caused by germline defects of mismatch repair (MMR) genes. Endometrial cancer is the most common extracolonic neoplasm in HNPCC and is the primary clinical manifestation of the syndrome in some families. The cumulative incidence of endometrial cancer among HNPCC mutation carriers is high, estimated to be from 22 to 43%. We hypothesized that women with double primary cancers of the colorectum and endometrium are likely to be members of HNPCC families. In order to determine how frequently HNPCC manifests in the context of double primary cancers, we examined alterations of two MMR genes, hMSH2 and hMLH1, in 40 unrelated women affected with double primary cancers. These cases were identified using hospital-based and population-based cancer registries in Ontario, Canada. MMR gene mutations were screened by single-strand conformation polymorphism analysis and confirmed by direct sequencing. Eighteen percent (seven of 40) were found to harbor mutations of one of the two MMR genes. Analysis of colorectal and/or endometrial tumors of mutation-negative probands found microsatellite instability in seven of 20 cases. Six of seven mutation-positive probands had strong family histories suggestive of HNPCC. First degree relatives of mutation-positive probands had a very high relative risk (RR) of colorectal cancer (RR = 8.1, CI 3. 5-15.9) and endometrial cancer (RR = 23.8, CI 6.4-61.0). The relative risk of mutation-negative cases was 2.8 (CI 1.7-4.5) for colorectal cancer and 5.4 (CI 2.0-11.7) for endometrial cancer. We recommend that all double primary patients with cancers at these sites should have a genetic evaluation, including molecular analysis for HNPCC where appropriate.
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PMID:Mismatch repair gene defects contribute to the genetic basis of double primary cancers of the colorectum and endometrium. 1019 71

Most hereditary non-polyposis colorectal cancer (HNPCC) is due to germline mutations in DNA mismatch repair genes. Tumors arising as a result of these mutations display instability in microsatellites, which are short tandem repeats of DNA that are distributed throughout the genome. Although a subset of sporadic colorectal carcinomas also have microsatellite instability (MSI), the phenotype is a useful screening test in identifying patients with HNPCC caused by mutations in mismatch repair (MMR) genes. Studies have shown that some microsatellite markers are more efficient than others in identifying tumors with MSI. Furthermore, the frequency of instability can be assessed by categorizing patients into high (MSI-H, >/= 30-40% positive markers), low (MSI-L), and microsatellite stable (MSS) groups. Using a panel of 28 microsatellite markers, tumor and normal DNA from 10 HNPCC patients was used to identify the five most efficient markers for detecting MSI (BAT26, D2S123, FGA, D18S35, and TP53-DI). Each of the five markers detected MSI in 80-100% of the cases examined. We then expanded the sample size to 17 tumors from HNPCC patients. Each case had evidence for a mutation in either hMSH2 or hMLH1. We compared the efficiency of our panel of five best markers with another panel of five markers (BAT25, BAT26, D2S123, D17S250, and D5S346) identified as being efficient markers for detection of MSI at a recent NCI workshop. Our five selected markers were more efficient (85% vs. 79%) in detecting MSI. However, using either panel, 100% of the cases fell into the MSI-H category and the probability of misclassifying an MSI-H case as MSI-L is very low (0.002-0.008). We also examined four cases meeting the Amsterdam criteria for HNPCC, but with no evidence for mutation in either the hMSH2 or hMLH1 gene. With our panel, three were classified as MSI-H, while only two were classified as such with the NCI reference panel. The probability of misclassifying an MSI-L case as an MSI-H, using a panel of five markers is high (0.263).
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PMID:Loci for efficient detection of microsatellite instability in hereditary non-polyposis colorectal cancer. 1020 81

One of the earliest references to heredity in colorectal cancer dates to Aldred Warthin's now-famous recollection of his seamstress' distress regarding "cancer excess" in her family history. Her prediction of an early demise secondary to cancer of the female organs, colon, or stomach proved true. The slow, arduous investigation that ensued followed a tortuous route of nearly eight decades before the implications of such family histories were widely acknowledged through the designation of hereditary nonpolyposis colorectal cancer or Lynch Syndrome Variants I and II. The story of hereditary nonpolyposis colorectal cancer is one of chance meetings, the selfless sharing of information, perseverance in the face of adversity, meticulous scientific documentation, and ultimate vindication by a scientific process that yielded molecular genetic evidence through the identification of the culprit mutations (hMSH2, hMLH1, hPMS2, and hMSH6). Our purpose is to provide a brief outline of the course charted by the study of the genetics of hereditary nonpolyposis colorectal cancer. This should be of particular interest to the readers of this Journal as we celebrate 100 years of dedication to the diagnosis and treatment of diseases of the colon, rectum, and anus through the efforts of The American Society of Colon and Rectal Surgeons.
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PMID:A century of progress in hereditary nonpolyposis colorectal cancer (Lynch syndrome). 1021 13

Deficiency in DNA mismatch repair (MMR) is found in some hereditary (hereditary nonpolyposis colorectal cancer) and sporadic colon cancers as well as other common solid cancers. MMR deficiency has recently been shown to impart cellular resistance to multiple chemical agents, many of which are commonly used in cancer chemotherapy. It is therefore of interest to find an approach that selectively targets cells that have lost the ability to perform MMR. In this study, we examine the response of MMR-proficient (hMLH1+) and MMR-deficient (hMLH1-) colon carcinoma cell lines to the halogenated thymidine (dThd) analogues iododeoxyuridine (IdUrd) and bromodeoxyuridine (BrdUrd) before and after irradiation. These dThd analogues are used clinically as experimental sensitizing agents in radioresistant human cancers, and there is a direct correlation between the levels of dThd analogue DNA incorporation and tumor radiosensitization. In contrast to the well-characterized, marked increase in cytotoxicity (> 1 log cell kill) found with 6-thioguanine exposures in HCT116/3-6 (hMLH1+) cells compared to HCT116 (hMLH1-) cells, we found only modest cytotoxicity (10-20% cell kill) in both cell lines when treated with IdUrd or BrdUrd for 1 population doubling. Upon further analysis, the levels of halogenated dThd analogues in DNA were significantly lower (two to three times lower) in HCT116/3-6 cells than in HCT116 cells, and similar results were found in Mlh1+/+ spontaneously immortalized murine embryonic fibroblasts and fibroblasts from Mlh1 knockout mice. As a result of the higher levels of the dThd analogue in DNA, there was an increase in radiation sensitivity in HCT116 cells but not in HCT116/3-6 cells after pretreatment with IdUrd or BrdUrd when compared to treatment with radiation alone. Additionally, we found no differences in the cellular metabolic pathways for dThd analogue DNA incorporation because the enzyme activities of dThd kinase and thymidylate synthase, as well as the levels of triphosphate pools, were similar in HCT116 and HCT116/3-6 cells. These data suggest that the hMLH1 protein may participate in the recognition and subsequent removal of halogenated dThd analogues from DNA. Consequently, whereas MMR-deficient cells and tumor xenografts have shown intrinsic resistance to a large number of chemotherapeutic agents, the 5-halogenated dThd analogues appear to selectively target such cells for potential enhanced radiation sensitivity.
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PMID:The mismatch repair protein, hMLH1, mediates 5-substituted halogenated thymidine analogue cytotoxicity, DNA incorporation, and radiosensitization in human colon cancer cells. 1021 89

Microsatellite instability (MSI) has been described in tumors from patients with hereditary nonpolyposis colorectal cancer, sporadic colorectal cancer, and other types of cancers. MSI is caused by the dysfunction of mismatch repairs genes. Loss of expression and mutation in one of the major mismatch repair genes, hMLH1, and the methylation of CpG sites in its promoter occur frequently in primary tumors and cell lines of colorectal cancer with MSI. To understand the mechanisms involved in the silencing of hMLH1 expression by methylation, we examined the methylation status of all CpG sites in the hMLH1 promoter in 24 colorectal cancer cell lines by the NaHSO3-sequencing method. We identified a small proximal region (-248 to -178, relative to the transcription start site) in the promoter in which the methylation status invariably correlates with the lack of hMLH1 expression. This correlation was further supported by the observation that cell lines that showed methylation-suppressed hMLH1 expression can be induced to reexpress hMLH1 by a methyl transferase inhibitor, 5-aza-2'-deoxycytidine, and the small region that we identified exhibited significant demethylation in all cell lines examined.
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PMID:Methylation of CpG in a small region of the hMLH1 promoter invariably correlates with the absence of gene expression. 1023 80

In this article, we describe the characteristics of 12 human colorectal-carcinoma cell lines established from 6 primary tumors and 6 metastatic sites of 11 Korean colorectal-carcinoma patients, including the morphology in vivo and in vitro and mutations of K-ras2, p15, p16, p53, APC, beta-catenin, hMLH1 and hMSH2 genes in vitro. No lines were contaminated with Mycoplasma or bacteria. All lines were proven to be unique by DNA-fingerprinting analysis. All lines expressed the surface carcino-embryonic antigen and secreted it into the supernatant fluid. The morphological correlation between the original tumors and cultured cells suggested that the original tumors showing mucinous adenocarcinoma correlated with floating aggregates in culture, and degree of desmoplasia in the original tumor correlated with attached growth in culture. Five of the cell lines showed mutations in the K-ras2 gene, and 6 of the cell lines showed mutations in the p53 gene. The p15 gene was deleted in 2 cell lines, and the p16 gene was hypermethylated in 3 cell lines. The mutation of mismatch-repair genes (hMLH1 and hMSH2) was found in 4 lines, the APC gene and beta-catenin gene were mutated in 9 and 2 lines respectively. These well-characterized colorectal-cancer cell lines should serve as useful tools for investigating the biological characteristics of colorectal cancer.
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PMID:Establishment and characterization of 12 human colorectal-carcinoma cell lines. 1036 37

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