Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The coding sequences of multiple human tumor suppressor genes include microsatellite sequences that are prone to mutations. Saccharomyces cerevisiae strains deficient in DNA mismatch repair (MMR) can be used to determine de novo mutation rates of these human tumor suppressor genes as well as any other gene sequence. Microsatellites in human TGFBR2, PTEN and APC genes were placed in yeast vectors and analyzed in isogenic yeast strains that were wild-type or deletion mutants for MSH2 or MLH1. In MMR-deficient strains, the vector containing the (A)(10) microsatellite sequence of TGFBR2 had a mutation rate (mutations/cell division) of 1.4 x 10(-4), compared to a mutation rate of 1.7 x 10(-6) in the wild-type strain. In MMR-deficient strains, mutation rates in PTEN and APC were also elevated above background levels. PTEN mutation rates were higher in both msh2 (4.4 x 10-5) and mlh1 strains (2.3 x 10-5). APC mutation rates in the msh2 strain (2.4 x 10-6) and the mlh1 strain (1.7 x 10-6) were also significantly, but less dramatically, elevated over background. Mutations selected for in the yeast screen were identical to those previously observed in human tumor samples with microsatellite instability (MSI). This functional assay has applicability in providing quantitative data about microsatellite mutation rates caused by MMR deficiency in any human tumor suppressor gene sequence. It can also be applied as a genetic screen to identify new genes that are vulnerable to such microsatellite mutations and thus may be involved in the neoplastic development of tumors with MSI.
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PMID:A functional assay for mutations in tumor suppressor genes caused by mismatch repair deficiency. 1173 38

Colorectal cancer is the most common malignant tumor in the french population. This tumor represents 45% of the cancers of the digestive tract in female and 60% in male. It is one of the main problem in the field of Public Health but recent progress for research, prophylaxis and treatment have been performed. There are two different pathogenic pathways for colorectal cancer. In chromosomal instability a sequence of rearrangements leads step by step from normal to adenoma and to carcinoma. It is the common pathway observed in 85% of colorectal cancers, mainly localized in left colon. In genic nucleotidic instability loss of tumor-suppresor genes and activation of cellular oncogenes are the consequence of DNA mismatch repair system, which is controlled by several genes. The defect of DNA mismatch repair leads to a hypermutable state in which simple repetitive DNA sequences are specially instable. This is the basis for a test to demonstrate nucleotidic instability. This pathway is found in the remaining 15% of colorectal cancers which are mainly localized on right colon. A mutational inactivation of both alleles of APC gene is considered as an initial gatekeeper event although some cancers begin with a mutation in beta-catenin gene which has the same functional impact. APC expression plays central role in regulating the rate of beta-catenin degradation. Destruction of beta-catenin prevents its translocation into the nucleus where it promotes cellular proliferation. About 5% of colorectal cancer are developed in a high risk population, Familial Adenomatous Polyposis coli (FAP) or Hereditary Non Polyposis Colon Cancer (HNPCC). FAP is caused by a germline mutation in APC gene. Every cell harbors a mutation of an APC allele which insures that a large number of adenomas will occur once an inactivating event occurs on the other wild-type APC allele. The demonstration of a constitutional mutation in a family allows to limit the survey only to the carriers. The phenotypic expression (attenuated, profuse, associated with extra-intestinal lesions) is correlated with the site of the APC mutation. Thus the determination of this site occurs in the choice of the treatment. HNPCC is suggested on clinical and genealogical criterions (young age of onset of cancer, multiple family members affected with cancer in multiple generations, the association of certain tumors in an individual of family, multiple tumors). A biological test may be useful to demonstrate the nucleotidic instability (MSI: microsatellite instability). Constitutional mutations on the mismatch repair genes, mainly MSH2 and MLH1, cause HNPCC syndrome. Endometrial and urethelial malignant tumors are frequent in an individual or in the family. The proven or suspected carriers of mutations undergo colonoscopic surveillance every 1 to 2 years, starting at age 25. An anti-tumoral action of the non steroidal antiinflammatory drugs (NSAID) is now recognized. Firstly observed in animal models of colon cancer the suppressive action was demonstrated in patient with Familial Adenomatous Polyposis. From the results of several epidemiological studies the suppressive action can be generalized to common intestinal tumors. This effect is in relation with the cyclooxygenase 2 inhibition. Other independent pathways intervene: NSAID interfere with beta-catenin, decreasing its action on cellular division. The indication of NSAID and more specifically of COX2 inhibitors in the prophylaxis of colo rectal cancer are yet questioned. The results of trials in progress are expected.
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PMID:[Recent notions on intestinal cancerogenesis, their implications in genetic risk screening and preventive action of non-steroid anti-inflammatory agents]. 1214 48

Colorectal cancers (CRC) among Israeli Arabs differ from those diagnosed in Jewish Israeli individuals in two manners: an earlier age of occurrence and a low frequency. These differences are unaccounted for and thus prompted us to perform genetic analysis in Israeli Arab CRC patients. Analysis included the major Hereditary non-polyposis colorectal cancer (HNPCC) genes and the APC I1307K mutation (MIM# 175100.0029). Twenty-five patients and 25 relatives from 24 unrelated families were clinically classified according to personal and familial cancer history. If MSI (microsatellite instability) was displayed in tumor tissue, patients underwent mutation analysis of the MSH2 and MLH1 genes using DGGE (denaturing gradient gel electrophoresis) and sequencing. MSI was detected in 9/21 of the tumors tested (43%). Two novel missense mutations were diagnosed among 11 fully analyzed patients: a change of A to G at position 380 in MSH2 (N127S), and a D601G mutation in MLH1. The I1307K mutation was detected in 8 families (8/24, 33.3%). This is the first report of genetic analysis in familial CRC associated genes among Israeli Arabs. We suggest that the I1307K mutation may contribute to CRC in Israeli Arabs and that inactivating mutations of MSH2 and MLH1 may not be a major cause for early onset CRC.
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PMID:Genetic analysis of familial colorectal cancer in Israeli Arabs. 1265 64

Topics discussed here include PTEN mutations and colonic polyps; WNT signaling, APC, beta-catenin, and gastrointestinal neoplasms; mismatch-repair genes (MLH1, MSH2, PMS1, MSH6) and hereditary nonpolyposis colorectal cancer; MYH mutations and autosomal recessive colorectal tumors; STK11 mutations and Peutz-Jeghers syndrome; TGFbeta and gastrointestinal cancer; BMPR1A mutations and juvenile polyposis; FGF/FGFR alterations in gastrointestinal neoplasms; PTCH mutations and gastrointestinal neoplasms; RUNX3 expression and gastric cancer; role of mucins in gastric carcinogenesis; KIT, PDGFRalpha, and gastrointestinal stromal tumors; intestinal neurofibromatosis; and gastrointestinal tumors in other disorders.
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PMID:Molecular dimensions of gastrointestinal tumors: some thoughts for digestion. 1451 68

Colorectal cancer is a complex disease from a genetic point of view because both genetic and environmental factors interact in its development. Only familial adenomatous polyposis (FAP) follows mendelian genetics, in that mutations of the APC gene lead to development of the tumours. Lynch syndrome is the most frequent form of hereditary colorectal cancer and appears to be associated with other types of extracolonic cancers. The genetic basis has been established as a defect in DNA mismatch repair genes, and there is genetic heterogeneity due to the involvement of several genes in this system. Germinal mutations in these genes predispose to appearance of the syndrome. The aim of this study is to describe the tumoral spectrum of 10 families, comprising a total of 488 individuals, from the island of Tenerife (Canary Islands) and to assess whether the geographical isolation of this population has changed any features of the tumoral spectrum of the syndrome in comparison with studies that cover larger geographical areas with more genetic exchange. From our results we can conclude that the genetic drift and consanguinity in this population with a demographic history of isolation did not significantly alter the tumoral spectrum of the syndrome. Our data confirm that families affected by Lynch syndrome are a high-risk population and should be closely monitored, since their careful supervision has been shown to be useful in preventing cancer. We also emphasize the importance of developing a complete family history that permits these families to be identified together with a mutational screening of DNA mismatch repair genes (mainly MLH1 and MSH2 genes) with the aim of a possible identification of members of a family that should be carefully monitored (the carriers of germline mutations in these genes), whereas the remaining members, originally, are no more at risk than the general population.
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PMID:Tumour spectrum of non-polyposis colorectal cancer (Lynch syndrome) on the island of Tenerife and influence of insularity on the clinical manifestations. 1507 85

The hereditary predisposition to cancer dates historically to interest piqued by physicians as well as family members wherein striking phenotypic features were shown to cluster in families, inclusive of the rather grotesque cutaneous findings in von Recklinghausen's neurofibromatosis, which date back to the sixteenth century. The search for the role of primary genetic factors was heralded by studies at the infrahuman level, particularly on laboratory mouse strains with strong susceptibility to carcinogen-induced cancer, and conversely, with resistance to the same carcinogens. These studies, developed in the 19th and 20th centuries, continue today. This article traces the historical aspects of hereditary cancer dealing with identification and ultimate molecular genetic confirmation of commonly occurring cancers, particularly of the colon in the case of familial adenomatous polyposis and its attenuated form, both due to the APC germline mutation; the Lynch syndrome due to mutations in mismatch repair genes, the most common of which were found to be MSH2, MLH1, and MSH6 germline mutations; the hereditary breast-ovarian cancer syndrome with BRCA1 and BRCA2 germline mutations; the Li-Fraumeni (SBLA) syndrome due to the p53 mutation; and the familial atypical multiple mole melanoma in association with pancreatic cancer due to the CDKN2A (p16) germline mutation. These and other hereditary cancer syndromes have been discussed in some detail relevant to their characterization, which, for many conditions, took place in the late 18th century and, in the more modern molecular genetic era, during the past two decades. Emphasis has been placed upon the manner in which improved cancer control will emanate from these discoveries.
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PMID:Inherited predisposition to cancer: a historical overview. 1526 68

The classical paradigm of mutation screening seeks to relate alterations in DNA sequence to their effect at the protein level. However, the majority of missense mutations are problematic as their pathological significance is often unclear. In order to test the hypothesis that many missense mutations primarily cause defects at the RNA rather than the protein level, we have performed retrospective RNA analysis of 12 individuals carrying missense mutations in the cancer predisposition genes APC, BRCA1, BRCA2, MLH1, and MSH2. RNA was extracted from peripheral blood samples and RT-PCR performed in order to assess the splicing and expression of the mutant allele in each case. Four of the 12 missense mutations analysed were associated with RNA defects. We detected two cases of exon skipping and one case of partial intron inclusion with activation of a cryptic intronic splice site in MLH1. A fourth case was associated with monoallelic expression of BRCA1. In addition, allele-specific analysis of common coding polymorphisms identified a further case of monoallelic BRCA1 expression in one of two individuals who had previously screened as mutation-negative. Although we were unable to identify the underlying cause of this loss of expression, it strongly suggests the presence of a pathogenic defect in BRCA1 in this case, highlighting the use of allelic expression studies as a method of mutation scanning. Finally, we used our dataset to test the ability of several in silico sequence analysis tools to identify splicing defects. Our results suggest that a significant number of missense mutations in cancer predisposition genes are associated with defects of RNA splicing, and that the use of gene- and splice site prediction software can aid in identifying such mutations.
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PMID:RNA analysis reveals splicing mutations and loss of expression defects in MLH1 and BRCA1. 1530 Aug 54

It is important to evaluate the effects of proposed interventions to reduce the risk of disease among carriers of a highly penetrant mutation, such as the mutations in BRCA1 and BRCA2 for breast and ovarian cancers or in APC and MLH1 or MSH2 for colon cancer. However, some studies that evaluate the effects of interventions designed to reduce risk in mutation carriers may be susceptible to a serious selection bias when they are based in clinics that care for persons at high risk for the disease. A study design in which a large fraction of the case patients were diagnosed before being seen at the clinic and all control subjects are persons previously seen at the clinic can create a false impression of intervention efficacy if, as is likely, mutation carriers seen at the clinic were more likely to receive the intervention than mutation carriers in the general population.
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PMID:Bias in intervention studies that enroll patients from high-risk clinics. 1531 55

Familial adenomatous polyposis patients, who have a germline APC mutation, develop adenomas in normal-appearing colonic mucosa, and in the process usually acquire a mutation in the other APC allele as well. Nonetheless, the cellular mechanisms that link these initiating genetic changes with the earliest tissue changes (upward shift in the labeling index) in colon tumorigenesis are unclear. Based on the tenet that colorectal cancer originates from crypt stem cells (SCs) and on our kinetic modeling, we hypothesized that overpopulation of mutant colonic SCs is the missing link. Directly testing this hypothesis requires measuring changes in the size of the SC population, but specific markers for human colonic SCs are lacking. Hence, we used immunohistochemical mapping to study crypt base cells, of which SCs are a subset. Using colectomy specimens from 16 familial adenomatous polyposis and 11 control cases, we determined the topographic profiles of various cell populations along the crypt axis and the proportions of each cell type. In the formation of adenomatous crypts, the distribution of cells expressing crypt base cell markers (MSH2, Bcl-2, survivin) expanded toward the crypt surface and showed the greatest proportional increase (fivefold to eightfold). Cells expressing a marker for the upper crypt (p27(kip1)) shifted to the crypt bottom and showed the smallest increase. This suggests that: 1) during adenoma development, APC mutations cause expansion of the crypt base cell population, including crypt SCs; 2) SC overpopulation can explain the shifts in pattern of proliferative crypt cell populations in early colon tumorigenesis, and 3) mutant crypt SCs clonally expand to form colonic adenomas and carcinomas.
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PMID:Colonic crypt changes during adenoma development in familial adenomatous polyposis: immunohistochemical evidence for expansion of the crypt base cell population. 1550 20

The observed increased incidence of colorectal cancer in Ashkenazi Jews compared to other populations is unexplained but likely has a genetic component. The I1307K APC polymorphism/mutation is carried by 6-8% of Ashkenazim and increases the risk of colorectal cancer 1.5-2 fold. There are few differences between the phenotype of colorectal cancer in I1307K carriers and sporadic cases. It is estimated that the mutation accounts for 6% of cases of colorectal cancer in Jews of Eastern European heritage. It should not be the subject of mass screening in Ashkenazi Jews, although it may be important in cases of familial colorectal cancer. Even rarer is the 1906G-->C MSH2 mutation carried by less than 1% of Ashkenazim, but as with other HNPCC mutations likely associated with a high risk of malignancy. Mutations at 15q13-14 are associated with the colorectal adenoma and carcinoma syndrome (CRAC) described in Ashkenazi families. The prevalence of the mutation is not known, nor its significance as a cause of colorectal cancer. Despite the paucity of genetic explanations for the high risk of colorectal cancer in Ashkenazim, that risk warrants aggressive colorectal cancer screening and particular attention to family history of malignancy in all Jews of Ashkenazi descent.
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PMID:Genetic factors and colorectal cancer in Ashkenazi Jews. 1551 44


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