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 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

Defective DNA mismatch repair in human tumors leads to genome-wide instability of microsatellite repeats and a molecular phenotype referred to as microsatellite instability (MSI). MSI has been reported in a variety of cancers and is a consistent feature of tumors from patients with hereditary non-polyposis colorectal cancer. Approximately 20% of cancers of the uterine endometrium, the fifth most common cancer of women world-wide, exhibit MSI. Although the frequency of MSI is higher in endometrial cancers than in any other common malignancy, the genetic basis of MSI in these tumors has remained elusive. We investigated the role that methylation of the MLH1 DNA mismatch repair gene plays in the genesis of MSI in a large series of sporadic endometrial cancers. The MLH1 promoter was methylated in 41 of 53 (77%) MSI-positive cancers investigated. In MSI-negative tumors on the other hand, there was evidence for limited methylation in only one of 11 tumors studied. Immunohistochemical investigation of a subset of the tumors revealed that methylation of the MLH1 promoter in MSI-positive tumors was associated with loss of MLH1 expression. Immunohistochemistry proved that two MSI-positive tumors lacking MLH1 methylation failed to express the MSH2 mismatch repair gene. Both of these cancers came from women who had family and medical histories suggestive of inherited cancer susceptibility. These observations suggest that epigenetic changes in the MLH1 locus account for MSI in most cases of sporadic endometrial cancers and provide additional evidence that the MSH2 gene may contribute substantially to inherited forms of endometrial cancer.
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PMID:MLH1 promoter methylation and gene silencing is the primary cause of microsatellite instability in sporadic endometrial cancers. 1007 35

An3 1 KAL I MutL homologue 1 (MLH1) is a member of the family of proteins required for DNA mismatch repair. Germ-line mutations in MLH1 lead to the cancer susceptibility syndrome hereditary nonpolyposis colorectal cancer (HNPCC). We generated mice carrying a null mutation in the Mlh1 gene. We showed that mice heterozygous and homozygous for the Mlh1 gene are predisposed to developing tumors of the gastrointestinal (GI) tract, lymphomas, and a number of other tumor types. We also examined the role of adenomatous polyposis coli gene (Apc) gene mutations in the GI tumors of Mlh1 mutant mice by different methods and showed that the GI tumors in Mlh1 mice express little or no adenomatous polyposis coli protein. When an Apc gene mutation was bred into the Mlh1 mutant mice, the GI tumor incidence increased 40-100-fold. The wild-type Apc allele in these tumors was found to contain mutations. Together, these results show that we have developed two mouse models for human HNPCC and that the mechanisms of tumor development in the GI tract of these mice involve loss of Apc gene function in a manner very similar to that seen in the GI tumors of HNPCC.
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PMID:Tumorigenesis in Mlh1 and Mlh1/Apc1638N mutant mice. 1009 63

Hereditary predisposition to non polyposis colorectal cancer is caused by a heterozygous germline mutation in a DNA mismatch repair gene (essentially hMLH1 or hMSH2). Cancer progression in predisposed individuals results from the occurrence of a somatic alteration of the normal copy of the gene. Recently, we identified children with a constitutional deficiency of mismatch repair activity, due to a homozygous germline mutation of the hMLH1 gene. These children exhibited clinical features of de novo neurofibromatosis type 1 and early onset of hematopoietic cancers. This observation demonstrates that mismatch repair deficiency is compatible with human development. However, the subsequent genetic instability leads to a high cancer susceptibility. In this context, the NF1 gene appears to be a preferential mutational target. Implications of this observation are discussed.
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PMID:[HNPCC syndrome, microsatellite instability and NF1 gene alteration]. 1057 31

To determine the role played by MLH1 and MSH2 missense variants in cancer susceptibility, we have investigated the following genetic and biological characteristics associated with six MLH1 and four MSH2 missense changes identified in Italian hereditary nonpolyposis colorectal cancer (HNPCC) families: co-segregation with disease phenotype and/or bonafide pathogenetic mutations; presence of the variant in healthy control subjects; evolutionary conservation of the involved aminoacid and type of aminoacid change; and presence/absence of microsatellite instability (MSI) in tumour DNA. Overall, nine variants did not fulfil > or = 2 pathogenicity criteria. MSI was investigated in tumour samples from carriers of nine different missense mutations. Only 3/9 variants were associated with MSI in tumour DNA. In addition, four variants were not present in affected pedigree members, and five variants were observed in the control population. Based upon these results, we conclude that most MLH1 and MSH2 missense changes are unlikely to act as major causative factors in colorectal cancer susceptibility and development.
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PMID:Assessment of pathogenicity criteria for constitutional missense mutations of the hereditary nonpolyposis colorectal cancer genes MLH1 and MSH2. 1057 10

The last decade has seen many great successes in isolating genes involved in inherited disease, a process that is now scaled up by Human Genome Project. The identification of genes responsible for hereditary tumors has made it possible to do the genetic diagnosis of hereditary tumors. However, the benefits and limits of genetic testing for cancer susceptibility are different in each hereditary tumor. It is important to continue the analysis of significance(frequency and penetrance) of mutations of cancer predisposition genes and to make clear the genotype-phenotype and other correlation. Hereditary breast cancer and hereditary non-polyposis colorectal cancer are reviewed and the significance of genetic epidemiology of hereditary tumor is discussed.
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PMID:[Genetic epidemiology of hereditary tumor]. 1092 6

Colorectal cancer is a major cause of morbidity and mortality among types of cancer in the United States. Significant progress has been made in understanding the molecular mechanisms that lead to it. Much knowledge was obtained through study of genetic changes that occur in individuals with a familial predisposition to colorectal cancer, including familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) syndromes. The gene with mutations that result in FAP has been identified as adenomatous polyposis coli (APC). Similarly, mutations in several genes that normally function in DNA mismatch repair result in HNPCC. Colorectal cancer is the result of accumulated mutations in several additional oncogenes or tumor suppressor genes, and this information leads to the formulation of a genetic model for the disease. Recent studies have also identified a relatively prevalent polymorphism in the APC gene in Ashkenazi Jews that is associated with an increased risk for colorectal cancer. These studies present a paradigm based on the APC mutation (APC I1307K) for the screening of cancer susceptibility genes in the population at large. Currently available techniques for genetic testing of colorectal cancer are also discussed in this review, along with their ethical implications.
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PMID:The molecular genetics of colorectal cancer. 1098 Sep 85

There are at least nine major cancer susceptibility syndromes that infer an increased risk for colorectal cancer and/or colorectal polyposis; hereditary nonpolyposis colorectal cancer syndrome, Muir-Torre syndrome, Turcot syndrome, the I1307K polymorphism of the APC gene, familial adenomatous polyposis, attenuated familial adenomatous polyposis, Peutz Jeghers syndrome, juvenile polyposis, and the PTEN hamartoma tumor syndrome. As a result, the differential diagnosis of hereditary colorectal cancer can be complex. In addition, there has been a dramatic increase in the knowledge available regarding risk assessment and management of hereditary colorectal cancer syndromes. The literature was reviewed to develop this concise review of the hereditary colorectal cancer syndromes to facilitate the accurate diagnosis of each syndrome and the appropriate medical care for individuals with these diagnoses. Referral to a qualified Clinical Cancer Genetics program is appropriate if any of these syndromes is suspected and they will ensure the most up-to-date information is available to the patient, their family, and their health care professionals.
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PMID:Hereditary colorectal cancer: risk assessment and management. 1100 40

Mutations in the BRCA1 gene cause strongly elevated risks of breast and ovarian cancers but may also confer a 3-fold increased risk for colorectal cancer. To address the relationship between BRCA1 carriership and colorectal tumorigenesis, we studied the genetics of a breast-ovarian cancer family with 7 cases of colorectal cancer. A germline 3938insG mutation in BRCA1 was found in 5 breast-cancer patients, 1 with ductal carcinoma in situ, ovarian cancer and an adenoma of the colon, and in 4/5 colorectal-cancer patients investigated. However, the youngest patient, diagnosed at age 23, was a non-carrier. Loss of the wild-type BRCA1 allele was observed in 3/3 breast tissues (2 breast carcinomas and 1 ductal carcinoma in situ) but in 0/6 colorectal tissues (5 carcinomas and 1 adenoma), suggesting that BRCA1 loss is not critical for colorectal tumorigenesis. To examine the possibility that an as yet unknown gene linked to BRCA1 was involved in the colorectal cancers, chromosome 17 segregation was studied with 7 polymorphic markers encompassing a 20 cM region including BRCA1. None of these markers showed complete allele sharing among all 5 colorectal-cancer patients studied. Clinical history, mutation analysis and microsatellite instability analysis excluded a role for any of the known colorectal-cancer susceptibility genes. In 4 other Dutch families carrying the same BRCA1 mutation, only 1 colorectal-cancer case was reported, of which the carrier status is unknown.
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PMID:Genetic analysis of a breast-ovarian cancer family, with 7 cases of colorectal cancer linked to BRCA1, fails to support a role for BRCA1 in colorectal tumorigenesis. 1107 48

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant inherited cancer susceptibility syndrome signifying a very high risk of colorectal and endometrial cancer at young age. It also entails an increased risk of a variety of other tumours, such as ovarian, gastric, uroepithelial and biliary tract cancer. The underlying pathogenic mutation lies in one of the five known DNA mismatch repair genes (MSH2, MLH1, PMS1, PMS2, and MSH2). The majority of HNPCC patients and families can at present be identified and the underlying mutation detected by genetic diagnostics. This provides the opportunity for predictive genetic testing to exclude or identify the mutation carrier status of the family members at risk. Mutation-negative individuals can then be relieved from any extra cancer threat. For mutation-positive individuals a preventive surveillance programme offers substantial benefits in reducing the cancer incidence, almost precluding death of colorectal cancer and reducing overall mortality.
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PMID:Surveillance on mutation carriers of DNA mismatch repair genes. 1107 89


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