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)

Germline alterations in one of five human DNA mismatch repair genes (hMSH2, hMLH1, hPMS1, hPMS2, and hMSH6) cause hereditary nonpolyposis colorectal cancer. Mutation analyses of these genes reveal gene carriers with a high risk for colorectal cancer, who benefit from surveillance to prevent disease. Equally important, presymptomatic testing allows nondisposed individuals to discontinue surveillance. We tested different mutation screening methods to optimize mutation detection in hMSH2 and hMLH1. Affected members from a total of 142 unrelated colorectal cancer families were analyzed. Denaturant gradient gel electrophoresis (DGGE), RT-PCR, and the protein truncation test (PTT) were used to screen for mutations on a DNA or RNA basis, respectively. In addition, a mutation-specific test on genomic DNA was used to find the Finnish mutation no. 1, a deletion of hMLH1 exon 16. DGGE identified most of the mutations in the mismatch repair genes hMLH1 and hMSH2. The RNA-based techniques were used to identify large deletions; however, these were rare in our materials. We describe our compiled results and experience from all our mutation screening studies, as well as unpublished data from our last DGGE screening of 58 patients and RT-PCR and PTT screening of 73 patients.
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PMID:Various mutation screening techniques in the DNA mismatch repair genes hMSH2 and hMLH1. 1049 24

The discovery of genes responsible for inherited forms of colorectal cancer have the potential to improve cancer risk assessment and counseling. Germline mutations (nonsense, frameshift) of APC are associated with familial adenomatous polyposis, an autosomal dominant syndrome, clinically characterized by young onset, hundreds of adenomatous polyps in the colon, and increased risk for extracolonic tumors. Mutations in APC are also associated with forms of attenuated familial adenomatous polyposis. Germline mutations in five mismatch repair related genes (hMSH2, hMLH1, hMSH6, hPMS1, and hPMS2) cause hereditary nonpolyposis colorectal cancer and are associated with increased risk of somatic genetic alterations and high DNA microsatellite instability. Hereditary nonpolyposis colorectal cancer is characterized by young onset colorectal cancer, proximal colon location, and increased risk of extracolonic cancers. A missense mutation in APC (I1307K) is associated with some familial colorectal cancer in Ashkenazic Jews. For persons at risk for hereditary forms of colorectal cancer, testing algorithms and gene test interpretations depend on identification of the pedigree germline gene mutation. Careful evaluation of the kindred for characteristic aggregation of tumor types among affected individuals and the availability of affected persons for testing are important issues in implementing genetic testing and follow-up management. Case reports illustrate the importance of genetic counseling as a component of cancer genetic risk assessment. The genetic counseling process includes exploration of patient risk perception, sources of anxiety related to cancer risk, patient education (specific cancer-related issues, prevention/intervention options), discussion of possible gene test options, test limitations, and consequences of various gene test outcomes.
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PMID:Genetic testing and counseling for hereditary forms of colorectal cancer. 1063 Jan 80

Hereditary nonpolyposis colorectral cancer (HNPCC), an autosomal dominantly inherited predisposition for early onset colorectal cancer, accounts for at least 6% of all colorectal malignancies. HNPCC results from germ-line mutations in DNA mismatch repair (MMR) genes (hMSH2, hMLH1, hPMS1 and hPMS2) and is associated with a high rate of replication errors in tumor cells. Using PCR-SSCP, the protein truncation test and DNA sequencing we have analyzed the hMSH2 and hMLH1 genes in 10 Italian families that met the standard diagnostic criteria for HNPCC. We have identified three new mutations in the hMLH1 gene. One mutation consists in a deletion of one base pair at nucleotide 954 (954delC) in exon 11 that creates an early stop at codon 366 and is predicted to abolish normal protein function. The other two are missense mutations. Cys77Arg and Ser193Pro, that cause dramatic amino acid substitutions in two highly conserved MLH domains. The Cys77Arg mutation occurs within a domain (1-114 residues) that is very critical for MMR function. The Ser193Pro mutation occurs in a highly conserved central region of the MLH1 protein. No functional domains have yet been identified in this region. All mutant alleles cosegregate with the cancer phenotype.
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PMID:hMLH1 mutations in hereditary nonpolyposis colorectal cancer kindreds. Mutations in brief no. 182. Online. 1066 Mar 33

Deficiencies of MutL DNA mismatch repair-complex proteins (hMLH1, hPMS2, and hPMS1) typically result in microsatellite instability in human cancers. We examined the association patterns of MutL proteins in human epithelial cancer cell lines with (HCT-116, N87, SNU-1, and SNU-638) and without microsatellite instability (HeLa, AGS, KATO-III, and SNU-16). The analysis of hMLH1, hPMS2, and hPMS1 was performed using Northern blot, Western blot, and co-immunoprecipitation studies. Our data provide evidence that MutL proteins form two different complexes, MutL-alpha (hPMS2 and hMLH1) and MutL-beta (hPMS1 and hMLH1). Gastric and colorectal cancer cells lines with microsatellite instability lacked detectable hMLH1. Decreased levels of hMLH1 protein were associated with markedly reduced levels of hPMS2 and hPMS1 proteins, but the RNA levels of hPMS1 and hPMS2 were normal. In this study, we describe the association of hPMS1 with hMLH1 as a heterodimer, in human cells. Furthermore, normal levels of hMLH1 protein appear to be important in maintaining normal levels of hPMS1 and hPMS2 proteins.
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PMID:Identification of a second MutL DNA mismatch repair complex (hPMS1 and hMLH1) in human epithelial cells. 1074 5

Hereditary nonpolyposis colorectal cancer (NHPCC) is the most common form of inherited colon cancer and one of the most frequent autosomal dominant disorders. HNPCC presents an early onset of colorectal cancer (< 50 years), proximal localization of the colonic tumors, and high risk of developing multiple primary colorectal tumors as well as extracolonic tumors. This disease is caused by mutations in at least four DNA mismatch repair genes, (hMSH2, hMLH1, hPMS1 and hPMS2) and estimations indicate that it affects 1:200-1:2,000 people in the Western populations. The identification of the genes responsible for HNPCC has prompted the search for mutations in affected individuals. DNA from an affected member of a family was sent to a Dutch HNPCC Diagnosis Centre. This Centre reported a germinal mutation, which introduces a premature stopcodon and causes the production of a truncated protein. This particular mutation has not been previously registered in the database of mutations related to this disease. After the identification of the mutation in the index patient, we have developed a quick and efficient procedure for detecting mutations in the rest of the family. The methodology is based on the amplification of the exon 13 in the hMSH2 gene using a forward primer that abuts the mutation site and introduces the cutting sequence of the enzyme Haelll++ only in the wild type allele. At present, seventeen members of the family have been diagnosed and nine have been found to be affected. The methodology is simple, specific, sensitive, inexpensive and applicable in low complexity laboratories.
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PMID:[Diagnosis by directed mutagenesis of a mutation at the hMSH2 gene associated with hereditary nonpolyposis colorectal cancer]. 1096 7

Mutations in N-acetyltransferase 2 (NAT2), a highly polymorphic enzyme involved in the metabolism of xenobiotics and carcinogens, may affect risk for colorectal cancer (CRC), especially among individuals with germ-line mutations in DNA mismatch repair genes. We determined the NAT2 genotypes and allele frequencies for 86 individuals with CRC who had mutations in hMLH1, hMSH2, or hPMS1. No significant difference in time to onset was observed between rapid (NAT2*4) and slow (NAT2*5, NAT2*6, and NAT2*7) acetylators. However, when individuals were stratified separately by NAT2 polymorphism (NAT2*5, NAT2*6, and NAT2*7), those who were heterozygous at the mutant locus NAT2*7 after adjustment for the NAT2 mutant loci NAT2*5 and NAT2*6 had a significantly higher risk of CRC (hazard ratio, 2.96; P = 0.012) and all of the cancers (hazard ratio, 3.37; P = 0.00004) than individuals homozygous for wild type at the NAT2*7 allele. These findings suggest that NAT2 genotype may be an important factor in tumorigenesis of CRC and cancers related to hereditary nonpolyposis CRC among individuals with mismatch repair defects.
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PMID:Age-associated risk of cancer among individuals with N-acetyltransferase 2 (NAT2) mutations and mutations in DNA mismatch repair genes. 1124 17

Hereditary nonpolyposis colorectal cancer (HNPCC) is attributable to a deficiency of mismatch repair. Inactivation of DNA mismatch repair underlies the genesis of microsatellite instability in colorectal cancer. Germline mutations in three DNA mismatch repair genes, hMSH2, hMLH1, and hMSH6, have been found to segregate in HNPCC and HNPCC-like families. The two DNA mismatch repair genes hPMS1 and hPMS2 have also been suggested to predispose to HNPCC. In this study, 84 HNPCC and HNPCC-like kindreds without known mutations in the other three known DNA mismatch repair genes were screened for germline mutations in the hPMS1 or hPMS2 gene. No clear-cut pathogenic mutations were identified. Conversion technology was used to detect a large hMSH2 deletion in two affected members of the kindred in which the hPMS1 mutation was originally reported, whereas the hPMS1 mutation was only present in one of these two individuals. Since the hPMS1 and hPMS2 genes were first reported, germline mutations in hPMS2 have been demonstrated primarily in patients with Turcot's syndrome. However, no mutation in any of the two genes has been found to segregate in HNPCC families. Until there is better evidence for an increased colorectal cancer risk associated with germline mutations in these genes, a conservative interpretation of the role of mutations in these genes is advised.
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PMID:The role of hPMS1 and hPMS2 in predisposing to colorectal cancer. 1169 95

The hereditary non-polyposis colorectal cancer (HNPCC)-syndrome is the most common form of hereditary colorectal cancers, and accounts for 2-7% of the total colorectal cancer burden. Since there are no single clinical features specific for HNPCC, diagnosis is based on family history (Amsterdam or Bethesda criteria) and is confirmed by the detection of a mutation in one of the responsible mismatch repair (MMR) genes. Two types of HNPCC-families can be distinguished. Type I HNPCC tumors are exclusively located in the colon, whereas in Type II HNPCC patients, extracolonic tumors are present in the stomach, endometrium, ovary, and urinary tract. The identification of the human homologues of yeast mismatch repair genes hMSH2, hMSH3, hMSH6, hMLH1, hMLH3, hPMS1 (scMLH2), and hPMS2 (scPMS1) offered the prospect of genetic screening leading to an extensive search for mutations in HNPCC-families. The majority of the alterations have been found in hMSH2 (40%) and hMLH1 (40%) genes. Mutations in the other MMR genes appear rare, absent, and/or associated with atypical families (1-5%). As a result of the mismatch repair deficiency, replication misincorporation errors accumulate, resulting in a mutator phenotype. Diagnosis of HNPCC-associated replication errors is most easily determined by the examination of a panel of the National Cancer Institute (NCI)-recommended simple repeated sequences (microsatellites), combined with immunohistochemical analysis. Although the exact molecular mechanism of the tumor development in these patients remains poorly understood, the identification of tumors that harbor a microsatellite instability has clinical and prognostic implications.
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PMID:Mismatch repair and the hereditary non-polyposis colorectal cancer syndrome (HNPCC). 1185 92

Hereditary non-polyposis colorectal cancer (HNPCC), or Lynch syndrome I, is responsible for as high as 10% of all colorectal cancers (CRCs) newly diagnosed in any given year. This disorder has an autosomal dominant inheritance pattern and is almost fully penetrant (>85%). It occurs when there is a mutation in any one of six mismatch repair genes: hMLH1, hMSH2, hPMS1, hPMS2, hMSH3 and hMSH6. Mutations in these genes allow mistakes in tumor suppressor genes and oncogenes to accumulate which eventually leads to cancer. The founder of an HNPCC family in the Creighton University Hereditary Cancer Institute database was known to produce truncated hMLH1 protein, a product of one of the aforementioned mismatch repair genes. Lymphoblasts were isolated from ten members of this HNPCC family (six affected and four unaffected) and two persons from outside this family (both unaffected controls). RNA and DNA were purified from these lymphoblasts which had been transformed by the Epstein-Barr virus (EBV). The hypothesis was that a mutation in the hMLH1 gene perpetuated defects in its mRNA and functional protein. hMLH1 RNA transcripts were detected in reverse transcriptase polymerase chain reactions (RT-PCR) whereby total poly A(+) RNA was converted to a complementary DNA (cDNA), amplified using hMLH1 specific primers, purified and cycle sequenced. Likewise, DNA was employed as template for PCR amplification of hMLH1 exons; PCR products were then directly cycle sequenced. Affected family members were found to produce hMLH1 mRNA lacking exons 6 and 7 (and wild-type mRNA). A splicing mutation at 546--2 (two bases 5' to exon 7) was located in the genomic DNA samples from the six family members with the HNPCC phenotype. This mutation caused deletion of exon 7 from the mRNA. None of the four unaffected family members or the two unaffected persons outside of this family had the above defects in their hMLH1 mRNA and DNA.
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PMID:A hMLH1 genomic mutation and associated novel mRNA defects in a hereditary non-polyposis colorectal cancer family. 1205 1

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant, inherited condition that is characterized primarily by the development of early-onset colorectal cancer and a number of other epithelial malignancies. The underlying genetic basis of the disease is associated with a breakdown of DNA-mismatch repair. There are many genes involved in DNA-mismatch repair, and five of them have been implicated in HNPCC. Two of the genes (hMSH2 and hMLH1) account for the majority of HNPCC families (approximately 60%), and it is not known what the exact contributions of the remaining three genes (hPMS1, hPMS2, and hMSH6) are in relation to this condition. In addition, a sixth gene (hEXO1) has been associated with a disease phenotype that is consistent with HNPCC. Current estimates suggest that all four of these genes, combined, may account for up to 5% of families. In this report, we examine the contribution of hPMS2 and hEXO1 to a well-defined set of families that fulfill the diagnostic criteria for HNPCC. The genes, hPMS2 and hEXO1, were studied by denaturing high performance liquid chromatography (DHPLC) analysis in 21 families that have previously been determined not to have mutations in hMSH2 or hMLH1. hPMS2 accounts for a small proportion of HNPCC families, and none were deemed to be associated with hEXO1. Mutations in hPMS2 appear to account for a small proportion of families adhering to the Amsterdam II criteria, whereas hEXO1 does not appear to be associated with HNPCC.
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PMID:Hereditary non-polyposis colorectal cancer and the role of hPMS2 and hEXO1 mutations. 1552 88


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