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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 Colon Cancer Syndrome (HNPCC) is the most common cause of familial colorectal cancer. Molecular genetic studies of HNPCC have shown evidence of locus heterogeneity, and mutations in four genes (hMSH2, hMLH1, hPMS1, and hPMS2) which encode components of the mismatch enzyme repair system may cause HNPCC. To determine the extent and nature of locus heterogeneity in HNPCC, we performed genetic linkage studies in 14 HNPCC families from eastern and north-western England. Linkage to hMLH1 was excluded in six families, each of which were likely to be linked to hMSH2 (lod score > 1.0 in each family and total lod score for all six families = 7.64). Linkage to hMSH2 was excluded in three families, each of which were likely to be linked to hMLH1 (lod score > 1.0 in each family and total lod score at hMLH1 for all three families = 3.93). In the remaining five families linkage to hMSH2 or hMLH1 could not be excluded. These results confirm locus heterogeneity in HNPCC and suggest that, in the population studied, most large families with HNPCC will have mutations in hMSH2 or hMLH1. We did not detect any correlation between clinical phenotype and the genetic linkage results, but a Muir-Torre syndrome family excluded from linkage to hMLH1 was likely to be linked to hMSH2 and showed microsatellite instability in a tumour from an affected relative.
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PMID:Genetic linkage analysis in hereditary non-polyposis colon cancer syndrome. 761 41

Recent studies have demonstrated novel alterations of microsatellite DNA in tumor tissue. The alterations, termed microsatellite instability or replication error phenotype, have now been observed in tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC), the Muir-Torre syndrome (MTS) and in an increasing number of sporadic tumors. These observations, along with the use of genetic linkage analysis, have led to the identification of at least four genetic susceptibility loci for HNPCC, hMSH2, hMLH1, hPMS1 and hPMS2, each of which are involved in DNA mismatch repair. For those tumors demonstrating microsatellite instability, several different phenotypes may exist, the significance of which is currently unknown. Defective DNA mismatch repair may have important implications for the mechanism of tumorigenesis and the clinical behavior of tumors.
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PMID:Genomic instability in neoplasia. 762 Jan 21

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder characterized by the occurrence within a family of multiple cases of colorectal cancer in the absence of gastrointestinal polyposis. The prevalence of this syndrome is not yet clear, but it may account for 1%-5% of all colorectal cancers. Prior to the identification of the genetic basis of this syndrome, the disease was recognized by the familial aggregation of colorectal cancers that had an early age of onset, an excess of proximally located, and often multiple, primary tumors, and an excess occurrence of cancers in certain other organs. The recent description of an abnormality called "microsatellite instability," present in almost all cancers from HNPCC patients and in about 12%-15% of sporadic cases, led to a series of discoveries that linked this type of genomic instability to a defect in the DNA mismatch repair (MMR) system. Independent investigators have identified four HNPCC genes: hMSH2 (a homologue of the prokaryotic DNA MMR gene MutS) and hMLH1, hPMS1, and hPMS2 (all homologues of the prokaryotic DNA MMR gene MutL). Mutations in each of the four genes have been found in the germline cells of HNPCC families. A major target for research in this area is the development of clinically practical screening tests for the genetic carrier state of HNPCC.
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PMID:Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. 767 15

Hereditary nonpolyposis colorectal cancer (HNPCC) is a relatively common autosomal dominant cancer-susceptibility condition. The recent isolation of the DNA mismatch repair genes (hMSH2, hMLH1, hPMS1, and hPMS2) responsible for HNPCC has allowed the search for germ-line mutations in affected individuals. In this study we used denaturing gradient-gel electrophoresis to screen for mutations in the hMSH2 gene. Analysis of all the 16 exons of hMSH2, in 34 unrelated HNPCC kindreds, has revealed seven novel pathogenic germ-line mutations resulting in stop codons either directly or through frameshifts. Additionally, nucleotide substitutions giving rise to one missense, two silent, and one useful polymorphism have been identified. The proportion of families in which hMSH2 mutations were found is 21%. Although the spectrum of mutations spread at the hMSH2 gene among HNPCC patients appears extremely heterogeneous, we were not able to establish any correlation between the site of the individual mutations and the corresponding tumor spectrum. Our results indicate that, given the genomic size and organization of the hMSH2 gene and the heterogeneity of its mutation spectrum, a rapid and efficient mutation detection procedure is necessary for routine molecular diagnosis and presymptomatic detection of the disease in a clinical setup.
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PMID:Seven new mutations in hMSH2, an HNPCC gene, identified by denaturing gradient-gel electrophoresis. 772 59

Hereditary nonpolyposis colorectal cancer (HNPCC) is one of man's commonest hereditary diseases. Several studies have implicated a defect in DNA mismatch repair in the pathogenesis of this disease. In particular, hMSH2 and hMLH1 homologues of the bacterial DNA mismatch repair genes mutS and mutL, respectively, were shown to be mutated in a subset of HNPCC cases. Here we report the nucleotide sequence, chromosome localization and mutational analysis of hPMS1 and hPMS2, two additional homologues of the prokaryotic mutL gene. Both hPMS1 and hPMS2 were found to be mutated in the germline of HNPCC patients. This doubles the number of genes implicated in HNPCC and may help explain the relatively high incidence of this disease.
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PMID:Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. 807 30

Hereditary nonpolyposis colorectal cancer is caused by heritable defects in the DNA mismatch repair genes hMLH1, hMSH2, hPMS1, and hPMS2. We have used denaturing gradient gel electrophoresis to analyze the 19 exons and exon-intron borders of hMLH1 in 39 Swedish hereditary nonpolyposis colorectal cancer families. Germline mutations were found in eight of these families: two splice mutations affecting exons 3 and 7, respectively, and six missense mutations, of which, four were in exon 2 and one each were in exons 1 and 16. The relatively high number of missense mutations raises several important clinical and technical issues. Such alterations can be identified only when using methods that target DNA or mRNA sequence alteration because they do not cause protein truncations detected by in vitro translation assays. Furthermore, the relationship between these missense mutations and the predisposition to colon cancer is difficult to determine without additional information; thus, genetic counseling based on mutation data is difficult.
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PMID:Mutation screening in the hMLH1 gene in Swedish hereditary nonpolyposis colon cancer families. 852 98

Hereditary nonpolyposis colorectal cancer (HNPCC) is a common autosomal dominant cancer susceptibility condition. Inherited mutations in at least four DNA mismatch repair genes, hMSH2, hMLH1, hPMS1, and hPMS2, are known to cause HNPCC. In this study we used denaturing gradient gel electrophoresis (DGGE) to screen for hMLH1 mutations in 34 unrelated HNPCC families (30 Dutch, 3 Italian, and 1 Danish). Ten novel pathogenic germ-line mutations (seven affecting splice sites, two frameshifts, and one in-frame deletion of a single amino acid) have been identified in 12 (35%) of these families. In a previous study, hMSH2 mutations were found in 21% of the same families. While the spectrum of mutations at the hMSH2 gene among HNPCC patients appears heterogeneous, a cluster of hMLH1 mutations has been found in the region encompassing exons 15 and 16, which accounts for 50% of all the independent hMLH1 mutations described to date and for > 20% of the unrelated HNPCC kindreds here analyzed. This unexpected finding has a great practical value in the clinical scenario of genetic services.
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PMID:Majority of hMLH1 mutations responsible for hereditary nonpolyposis colorectal cancer cluster at the exonic region 15-16. 857 56

Hereditary non-polyposis colorectal cancer (HNPCC) predisposes to cancers of the colon, endometrium and several other extra-colonic sites in the absence of premonitory physical stigmata (Muir-Torre syndrome excepted). Discovery of the several DNA mismatch repair genes (hMSH2, hMLH1, hPMS1, hPMS2) holds the potential for determining the cancer destiny of patients, theoretically in utero. Pre-symptomatic DNA testing is now possible in patients from HNPCC families and will be clinically available once inexpensive and simple tests for these germ-line mutations have been effected. Genetic counseling will be mandatory, given the myriad socio-psychological, insurance, and potentially other personal issues which may impact this knowledge. New findings in the pathology of HNPCC, particularly an increased frequency of interval cancers and the likely accelerated rate of the adenoma to cancer sequence, indicate the need for more frequent colonoscopic surveillance with an option for prophylactic subtotal colectomy in germ-line-positive individuals.
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PMID:Overview of natural history, pathology, molecular genetics and management of HNPCC (Lynch Syndrome). 860 57

Hereditary nonpolyposis colorectal cancer (HNPCC) is a major cancer susceptibility syndrome known to be caused by the inheritance of mutations in DNA mismatch repair genes, such as hMSH2, hMLH1, hPMS1 and hPMS2. To investigate the role of genetic alterations of hMSH2 in HNPCC tumorigenesis, we analyzed 36 Japanese HNPCC kindreds as to hMSH2 germline mutations. Moreover, we also examined somatic mutations of hMSH2 or loss of heterozygosity at or near the hMSH2 locus in the tumors from the hMSH2-related kindreds. Germline mutations were detected in five HNPCC kindreds (5/36, 14%). Among them, three were nonsense mutations, one was a frameshift mutation and the other was a mutation in an intron where the mutation affected splicing. Loss of heterozygosity in four and somatic mutations in one were detected among the eight tumors with hMSH2 germline mutations. All these alterations were only detected in genomic instability(+) tumors, i.e., not in genomic instability(-) ones, indicating that mutations of hMSH2 were responsible for at least some of the tumors with genomic instability. These data establish a basis for the presymptomatic diagnosis of HNPCC patients, and constitute further evidence that both DNA mismatch repair genes and tumor suppressor genes may share the same requirement, i.e., two hits are necessary to inactivate the gene function.
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PMID:Loss or somatic mutations of hMSH2 occur in hereditary nonpolyposis colorectal cancers with hMSH2 germline mutations. 861 31

Colorectal cancer (CRC) has a strong familial component. Candidate genes for colorectal cancer have been identified through mutations in four mismatch repair genes (hMSH2, hMLH1, hPMS1, and hPMS2) and genes that are deleted or mutated in tumors (DCC, APC, and p53). Linkage analysis of candidate loci/regions was performed in 10 kindreds ascertained for common colorectal cancer from the Utah Population Database. Evidence for linkage to candidate genes was assessed using two- or three-point logarithm of the odds ratio scores with markers spanning the region of localization. One kindred is linked to hMSH2 and also fits the criteria for hereditary nonpolyposis colorectal cancer, having early age of onset and high penetrance for CRC. The remaining nine kindreds are unlinked to the candidate genes tested. These kindreds have a later age of onset and a lower penetrance than hereditary nonpolyposis colorectal cancer kindreds. these results indicate that further unmapped susceptibility loci may be responsible for much of the familial aggregation of CRC.
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PMID:Genetic heterogeneity and unmapped genes for colorectal cancer. 864 Aug 29


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