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

This paper provides an overview of the current approach to genetic counseling for cancer, using hereditary nonpolyposis colorectal cancer (HNPCC) as a prototype. Heretofore, when evaluating the possibility of an HNPCC diagnosis, physicians had to rely exclusively on a detailed family history of cancer in the context of an extended pedigree. Patients in the direct genetic lineage who had one or more first-degree relatives with an HNPCC syndrome cancer were told that they had a 50% likelihood of inheriting the deleterious gene. However, with the discovery of the HNPCC genes (hMSH2, hMLH1, hPMS1, hPMS2), genetic counseling can now provide a more precise determination of a patient's lifetime cancer destiny. Since these DNA findings are new, guidelines for sharing this information with patients remain preliminary. One must be certain that the patient wants to receive DNA information and that he or she is aware of potential discrimination by insurance companies and employers, as well as the possibility of psychological sequelae.
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PMID:Genetic counseling for hereditary cancer. 892 64

Mutations at the hMSH2 and hMLH1 mismatch repair loci have been implicated in the pathogenesis of colorectal cancer. Tumours with two allelic mutations at a mismatch repair locus develop replication errors (RERs). In the hereditary non-polyposis colorectal cancer (HNPCC) syndrome, one mutation is inherited and the other acquired somatically: in RER+ sporadic colorectal cancers, both mutations are somatic. RER+ tumours tend to have a low frequency of allele loss, presumably because they acquire most mutations through RERs. However, before a second mismatch repair mutation has occurred somatically, there is no reason to suppose that allele loss occurs less frequently in tumours that are to become RER+. Indeed, this second mutation might itself occur by allele loss. We have searched for allele loss at the hMSH2 and hMLH1 loci in RER+ and RER- sporadic colorectal cancers. Loss occurred at the hMLH1 locus in 7/17 (41%) RER+ tumours, compared with 6/40 (15%) RER- cancers (chi2=3.82, P approximately 0.05). At hMSH2, 2/22 RER+ sporadic cancers (9%) had lost an allele, compared with 2/40 (5%) RER- cancers (chi2=0.03, P>0.5). Taken together with previous studies which focused on colorectal cancers from HNPCC families, the data suggest that allele loss at hMLH1, but not at hMSH2, contributes to defective mismatch repair in inherited and sporadic colorectal cancer.
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PMID:Allele loss occurs frequently at hMLH1, but rarely at hMSH2, in sporadic colorectal cancers with microsatellite instability. 893 28

We analyzed the hMLH1 gene in 17 unrelated families with putative hereditary nonpolyposis colorectal cancer. The complete hMLH1 cDNA was amplified in one step, and after a second amplification, four overlapping segments were directly sequenced. We detected, in five families that did not meet the complete Amsterdam criteria, five alterations, including a double-base change resulting in a missense mutation (Lys-618-Ala), a splicing mutation affecting the intron 4 splice acceptor site, a 2-bp deletion at codon 726, a 7-bp deletion at codon 626, and a deletion of exons 13-16. The latter alteration was shown to result from a 22-kb genomic deletion due to a homologous recombination between Alu repeats located in introns 12 and 16. The detection of five germline hMLH1 mutations in five families that only partially fulfilled the Amsterdam criteria shows that these criteria do not allow the identification of all familial colorectal cancers due to mutations of the mismatch repair genes. The numerous Alu repeats present within the hMLH1 gene and the observation of large genomic deletions suggest that (a) Alu-mediated deletions might frequently be involved in hMLH1 inactivation, and (b) reverse transcription-PCR analysis, which allows the amplification of the entire coding region of the hMLH1 gene in one step, might be the most appropriate method for the detection of hMLH1 alterations.
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PMID:Identification of novel germline hMLH1 mutations including a 22 kb Alu-mediated deletion in patients with familial colorectal cancer. 897 Nov 83

A common form of human malignancy, hereditary non-polyposis colorectal cancer (HNPCC), as well as some sporadic human cancers, has been shown to exhibit frequent alterations in microsatellite sequences. This phenotype was ascribed to a defect in replication error correction, and indeed several tumour derived cell lines are deficient in mismatch repair. To date, four HNPCC loci, on chromosomes 2p, 2q, 3p and 7q, have been linked with genes designated hMSH2, hPMS1, hMLH1 and hPMS2, respectively, which encode proteins that display an extensive degree of sequence similarity to polypeptides involved in postreplicative mismatch correction in Escherichia coli and Saccharomyces cerevisiae. We have recently identified a new protein, GTBP, that is essential for mismatch repair in human cells. GTBP mutations are not associated with the profound MI commonly encountered in hereditary colon cancers. The roles of the proteins encoded by the individual mismatch repair genes in postreplicative mismatch correction and genome instability are discussed, with a view to assessing the potential utility of these findings in diagnosis of cancer predisposition and therapy.
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PMID:Mismatch repair and cancer. 897 28

Hereditary nonpolyposis colorectal cancer is a cancer susceptibility syndrome that has been found to be caused by mutations in any of several genes involved in DNA mismatch repair, including hMSH2, hMLH1, or hPMS2. Recent reports have suggested that hMSH2 and hMLH1 have a role in the regulation of the cell cycle. To determine if these genes are cell cycle regulated, we examined their mRNA and protein levels throughout the cell cycle in IMR-90 normal human lung fibroblasts. We demonstrate that the levels of hMSH2 mRNA and protein do not change appreciably throughout the cell cycle. Although hMLH1 mRNA levels remained constant, there was a modest (approximately 50%) increase in its protein levels during late G1 and S phase. The levels of hPMS2 mRNA fluctuated (decreasing 50% in G1 and increasing 50% in S phase), whereas hPMS2 protein levels increased 50% in late G1 and S phase. Our data indicate that, at least in normal cells, the machinery responsible for the detection and repair of mismatched DNA bases is present throughout the cell cycle.
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PMID:Cell cycle regulation of the human DNA mismatch repair genes hMSH2, hMLH1, and hPMS2. 900 May 55

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

Hereditary non-polyposis colorectal cancer (HNPCC) is a clinical syndrome characterised by an inherited predisposition to early onset colorectal and uterine cancers and an increased incidence of other cancers. It is caused by germline defects in the human mismatch repair genes. Defects in two of the known mismatch repair genes (namely hMSH2 and hMLH1) account for over 90% of mutations found in HNPCC families. In this study we have identified 14 families that fulfilled the clinical criteria for HNPCC and screened the hMSH2 and hMLH1 genes for germline mutations using single-strand conformational polymorphism (SSCP) analysis and DNA sequencing. Seven mutations were identified. Of these, there were five frameshifts, one missense mutation and a further novel mutation that involved separate transition and transversion changes in successive amino acid residues. Three of the mutations were in hMSH2 and four in hMLH1. The identification of germ-line mutations in an HNPCC family enables targeted surveillance and the possibility of early curative intervention. SSCP is a simple and effective method for identifying most mutations in the human mismatch repair genes using DNA from fresh, frozen or archival material.
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PMID:Use of SSCP analysis to identify germline mutations in HNPCC families fulfilling the Amsterdam criteria. 904 25

A genome-wide instability has been found in almost all analyzed malignant tumors from patients with hereditary non-polyposis colorectal cancer (HNPCC), and in a subgroup of sporadic (non-inherited) cancers of the same type. This mutator phenotype was initially seen as novel alleles at microsatellite loci (a family of repetitive DNA sequences) and was shown to be caused by mutations in the highly conserved mismatch repair genes. Mutations have been found in each of four of these human genes: hMSH2, hMLH1, hPMS1 and hPMS2, in the germline of HNPCC patients and in their tumors, as well as in sporadic tumors. These recent discoveries provide new molecular diagnostic tools for the detection of patients at high risk of developing carcinomas of the large bowel and other HNPCC-related tumors. Ongoing international research is progressively solving many of the unanswered questions at the genotypic and phenotypic levels of this newly identified mechanism in carcinogenesis.
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PMID:Microsatellite instability in human solid tumors. 906 3

Searching for mutations in DNA mismatch repair genes is important not only for presymptomatic diagnosis, but also for documenting the spectrum of mutations among families carrying predispositions to hereditary nonpolyposis colorectal cancer (HNPCC). We utilized an automated two-dimensional DNA typing system for mutational analysis of the hMLH1 gene and established optimal conditions for application of the technique to analysis of hMLH1. This approach enabled us to visualize 21 spots covering all 19 coding exons on a single gel and to envisage whether and where any mutations existed. All mutations that we had detected previously by other means in a panel of HNPCC patients and in one patient with sporadic endometrial cancer were also detectable by this method. Furthermore, using the 2-D system, we screened the entire coding regions of the hMLH1 gene in DNAs isolated from affected individuals belonging to two large HNPCC kindreds and four HNPCC-like kindreds, and from four patients with multiple primary cancers as well as eight sporadic colorectal cancers with replication error (RER)-positive phenotypes. We detected novel germline mutations in one HNPCC proband and one sporadic colorectal cancer with the RER-positive phenotype and one polymorphism in two HNPCC-like kindreds. This new diagnostic method is applicable to mutational analysis of any disease-causing gene, and it offers a major improvement over current approaches.
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PMID:Mutational analysis of the hMLH1 gene using an automated two-dimensional DNA typing system. 906 57

Microsatellite instability (or replication error phenotyp) is a new molecular phenotyp of a substantial fraction of human cancers. The microsatellite instability in these cancers arises from alterations in normal regions of the genome consisting short sequences of repeated DNA. Ubiquitous changes in length of microsatellite sequences between constitutional and tumor DNA occur in about 90% of cases of HNPCC and in about 15% of cases of non-familial, sporadic colorectal cancer. Microsatellite instability is also found in a substantial percentage of sporadic endometrial, and gastric cancer, as well as in additional sporadic cancers, such as lung cancer which is usually not associated with HNPCC. Thus far, four different mismatch repair genes (hPMS1, hPMS2, hMLH1 hMSH2), all homologous to bacterial DNA repair genes have been identified as involved in HNPCC kindreds, and consequently they are associated with microsatellite instability. In conclusion, these basic genetic informations provide new insights into a new molecular pathway in oncogenesis, i.e. the occurrence of mutations in genomic stability genes leading to an increased cellular mutation rate (replication error phenotyp) and thus to cancer.
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PMID:[Microsatellite instability--a new aspects in genetics and molecular biology of hereditary nonpolyposis and sporadic colorectal tumors]. 908 61


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