Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The panel of 60 human cancer cell lines (the NCI-60) assembled by the National Cancer Institute for anticancer drug discovery is a widely used resource. The NCI-60 has been characterized pharmacologically and at the molecular level more extensively than any other set of cell lines. However, no systematic mutation analysis of genes causally implicated in oncogenesis has been reported. This study reports the sequence analysis of 24 known cancer genes in the NCI-60 and an assessment of 4 of the 24 genes for homozygous deletions. One hundred thirty-seven oncogenic mutations were identified in 14 (APC, BRAF, CDKN2, CTNNB1, HRAS, KRAS, NRAS, SMAD4, PIK3CA, PTEN, RB1, STK11, TP53, and VHL) of the 24 genes. All lines have at least one mutation among the cancer genes examined, with most lines (73%) having more than one. Identification of those cancer genes mutated in the NCI-60, in combination with pharmacologic and molecular profiles of the cells, will allow for more informed interpretation of anticancer agent screening and will enhance the use of the NCI-60 cell lines for molecularly targeted screens.
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PMID:Mutation analysis of 24 known cancer genes in the NCI-60 cell line set. 1708 37

Colorectal cancer is a disease that originates from the neoplastic transformation of epithelial cells of the colon and rectum, as a result of the accumulation of genetic and epigenetic aberrations. At least four sequential genetic changes, affecting one oncogene (KRAS) and three tumor suppressor genes (APC, SMAD4 and TP53), are required for the development of colorectal cancer. Abundant experimental studies and epidemiological data, as well as several human clinical trials suggest a protective effect of Vitamin D against colon carcinogenesis. Hypercalcemia, a side effect of natural Vitamin D, has currently restricted its therapeutic use; however, the development of new synthetic analogs with reduced hypercalcemic activity is promising for cancer therapy and prevention. Extensive research to elucidate the mechanisms underlying the anti-cancer action of Vitamin D is being undertaken. Understanding the complex molecular and cellular networks induced by Vitamin D or its analogs will improve the use of these compounds for the prevention and treatment of colorectal cancer.
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PMID:Colorectal cancer: potential therapeutic benefits of Vitamin D. 1715 47

Research on developing molecular diagnostics for hereditary cancers resulted in establishing diagnostic services for familiar polyposis and non-polyposis patients (mutation determination of APC, MYH, STK11, SMAD4, MLH1, MSH2). In familiar testicular cancers the role of gr/gr gene on Y chromosome was identified. Molecular diagnostic tool was established to monitor the progression of follicular lymphoma using Bcl-2/IgH fusion sequences. Molecular diagnostic tools were developed to monitor circulating endothelial precursor cells (CEP) as well and the technique was tested in lung cancer patients. In malignant melanoma we have tested several potential novel markers among which ryanodine receptor seems to be a promising one, while the functional P2X7 receptor may serve as a therapeutic target. We have determined the tyrosine kinase "kinome" profile of HER-2-amplified breast cancers. Furthermore, the "kinome" profile was found to be characteristic for head and neck cancers of various anatomical location. Based on previous studies on the anti-migratory and antimetastatic potential of low-molecular-weight heparins, we have identified short heparin-derived oligosaccharides with maintained antimetastatic- but non-anticoagulant potentials. Pharmacogenomic studies on the role of polymorphism of the serine-hydroxymethyl-transferase (SHMT) gene in the efficacy of 5-FU and FOLFIRI protocols of colorectal cancer patients revealed a significant effect resulting in altered overall survival as well.
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PMID:[Developments in cancer management by innovative genomics. 2006 report of the National Cancer Consortium]. 1721 11

Tumors arising sporadically represent 70-80% of colorectal cancer (CRC). The two best defined forms of inherited CRC-familial multiple polyposis (FMP) and Hereditary Non-Polyposis Colon Cancer (HNPCC) account respectively for<1% and 2-3% of CRC. These rare genetic syndromes (FMP, HNPCC, Peutz-Jeghers Syndrome) are caused by major predisposing gene mutations (APC gene, MMR gene, BMPR1A. SMAD4,...) and local environmental factors play only a minor role. In the sporadic forms of CRC, 25% have significant genetic predisposition probably related to alleles with weak penetration (APC*I1307K, TGFbR1*6Ala...) and are more strongly affected by environmental factors.
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PMID:[Colorectal carcinogenesis. 1. Hereditary predisposition and colorectal cancer]. 1736 56

Colorectal cancer (CRC) is among the most prevalent and preventable forms of cancer worldwide, accounting for over 600,000 deaths in 2005. Both genetic and environmental factors contribute to cancer etiology and estimates suggest that at least one third of CRC has a familial component. There is increased awareness of a strong genetic component to CRC risk, with the identification of several high penetrance alleles that predict increased CRC susceptibility. These include familial adenomatous polyposis (FAP), linked to mutations or deletions of the APC tumor suppressor gene, as well as Lynch syndrome (formerly known as hereditary non-polyposis colorectal cancer or HNPCC), which is linked to mutations or deletions of one or more mismatch repair genes including MLH1, MSH2 and MSH6. In addition, mutations in genes encoding key signaling molecules have been linked to autosomal dominant hamartomatous syndromes that are associated with increased susceptibility to CRC. These include Peutz-Jeghers syndrome, which is linked to mutations in STK11/LKB and Juvenile polyposis, which is linked to mutations in the genes encoding SMAD4 and BMPR1A. In addition to these high penetrance autosomal dominant alleles, recessive mutations in the MYH mismatch repair gene are associated with a phenotype similar to FAP. With the widespread availability of genetic testing for these alleles, physicians will be faced with a complex array of choices in terms of advocating who should be tested, when should such testing take place, how it should be conducted and interpreted and why it changes the management and outcomes for the patient and his or her family.
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PMID:Genetic testing in colorectal cancer: who, when, how and why. 1739 93

Pathways of the molecular pathogenesis of colorectal carcinoma have been extensively studied and molecular lesions during the development of the disease have been revealed. High up in the list of colorectal cancer lesions are APC (adenomatous polyposis coli), K-ras, Smad4 (or DPC4-deleted in pancreatic cancer 4) and p53 genes. All these molecules are part of important pathways for the regulation of cell proliferation and apoptosis and as a result perturbation of these processes lead to carcinogenesis. The ubiquitin-proteasome system (UPS) is comprised of a multi-unit cellular protease system that regulates several dozens of cell proteins after their ligation with the protein ubiquitin. Given that among these proteins are regulators of the cell cycle, apoptosis, angiogenesis, adhesion and cell signalling, this system plays a significant role in cell fate and carcinogenesis. UPS inhibition has been found to be a pre-requisite for apoptosis and is already clinically exploited with the proteasome inhibitor bortezomib in multiple myeloma. Cyclooxygenase-2 (Cox-2) is the inducible form of the enzyme that metabolizes the lipid arachidonic acid to prostaglandin H2, the first step of prostaglandins production. This enzyme is up-regulated in colorectal cancer and in several other cancers. Inhibition of Cox-2 by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been found to inhibit proliferation of colorectal cancer cells and in epidemiologic studies has been shown to reduce colon polyp formation in genetically predisposed populations and in the general population. NSAIDs have also Cox-independent anti-proliferative effects. Targeted therapies, the result of increasingly understanding carcinogenesis in the molecular level, have entered the field of anti-neoplastic treatment and are used by themselves and in combination with chemotherapy drugs. Combinations of targeted drugs have started also to be investigated. This article reviews the molecular pathogenesis of colorectal cancer, the roles of UPS and Cox-2 in it and puts forward a rational for their combined inhibition in colorectal cancer treatment.
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PMID:Pathogenesis of colorectal carcinoma and therapeutic implications: the roles of the ubiquitin-proteasome system and Cox-2. 1748 76

Increased phosphorylation of FOXO1A, a FOXO transcription factor, has been implicated in several human cancers; however, it has not been studied in the gastric cancer to date. To determine the status of pFOXO1A expression in human gastric cancers and to determine its relationship with other tumor-associated proteins, we performed immunohistochemical staining on tissue array slides containing 272 human gastric carcinoma specimens. In non-neoplastic gastric mucosa, the expression of pFOXO1A was observed primarily in cells in the proliferative zone and in areas of intestinal metaplasia. In gastric carcinomas, the expression of pFOXO1A was observed in 230 (84.6%) out of 272 cases examined, and was positively correlated with the Ki-67-labeling index (P=0.026). The expression of pFOXO1A was higher in the early stages of pTNM (P<0.001), and was inversely correlated with the intestinal type by Lauren's classification (P=0.001), lymphatic invasion (P=0.017) and lymph node metastasis (P<0.001). Moreover, the expression of pFOXO1A was correlated with a longer patient survival (P=0.004). In addition, the expression of pFOXO1A was correlated with that of pAKT1 (P<0.001), PTEN (P=0.009), CDKN2A (P=0.012), APC (P=0.048), SMAD4 (P<0.001), CD82 (P=0.011), and BCL2 (P=0.011). In conclusion, our results showed that the expression of pFOXO1A is a frequent and early event in gastric tumorigenesis and that there is a significant correlation between pFOXO1A and better prognosis. Thus, our data suggest that the expression of pFOXO1A may serve as a valuable prognostic variable in gastric carcinoma and have significant implications for the development and application of targeted therapy.
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PMID:Constitutive phosphorylation of the FOXO1A transcription factor as a prognostic variable in gastric cancer. 1749 98

Approximately, a third of all colorectal cancer (CRC) is due to inherited susceptibility. However, high-risk mutations in APC, the mismatch repair (MMR) genes, MUTYH/MYH, SMAD4, ALK3 and STK11/LKB1 are rare and account for <5% of cases. Much of the remaining variation in genetic risk is likely to be explained by combinations of more common gene variants that modestly increase risk. Reliable identification of such 'low penetrance' alleles would provide insight into the aetiology of CRC and might highlight potential therapeutic and preventative interventions. In 2003, the National Study of Colorectal Cancer Genetics (NSCCG) was established with the aim of collecting DNA and clinicopathological data from 20,000 CRC cases and a series of spouse/partner controls, thereby creating a unique resource for identifying low-penetrance CRC susceptibility alleles. The National Cancer Research Network (NCRN) adopted NSCCG onto its portfolio of trials and 148 centres in the United Kingdom (UK) are now actively participating. Over 8,700 cases and 2,185 controls have so far been entered into NSCCG. Our experience in developing NSCCG serves to illustrate how world-class DNA databases for genetic analyses can be rapidly developed in the United Kingdom.
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PMID:National study of colorectal cancer genetics. 1789 93

In this study nine colorectal cancer cell lines were analysed by 10K SNP-arrays and spectral karyotyping (SKY). Complex chromosomal alterations and breakpoints of deleted or translocated fragments found by SKY could further be characterized by SNP-array analysis. Interestingly many monoallelic regions identified by SNP-array analysis display no copy number alterations, representing uniparental disomy (UPD). It was demonstrated that UPD seems to be involved in activation of early-acting tumor suppressor genes in MSS- (APC, CDKN2A) and MSI- (MLH1, MSH2, APC, CDKN2A) colorectal cancer cell lines. Genes involved later on in the adenoma-carcinoma sequence (i.e. TP53/SMAD4) were not found to be inactivated by UPD. Furthermore, identified amplified monoallelic regions may include oncogenes activated by allele-specific-amplification (i.e. Cyclin D1). However, at present, the majority of the monoallelic regions located in the present study have not yet been associated with known tumor suppressor genes and oncogenes. Further studies are warranted to identify relevant genes in the respective regions and to further verify the results presented here.
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PMID:SNP-Array genotyping and spectral karyotyping reveal uniparental disomy as early mutational event in MSS- and MSI-colorectal cancer cell lines. 1800 Mar 73

Over 90% of digestive tract malignancies are adenocarcinomas (ADC) and almost 95% of them have gastric (G), colorectal (CR) or pancreatic (P) localizations. The objectives of this work are to review the genetic abnormalities of ADC in these locations and their potential coincidences, along with the histogenetic correlation of their emergence. Genetic abnormalities affecting over 50% of cases include: in G-ADC, inactivation of suppressor genes of p53, APC and DCC tumor in its intestinal variant, hypoexpression of of caderine E in the diffuse variant and hyperexpression of cyclooxygenase-2 and cyclyn D in the intestinal form; in in CR-ADC, inactivation of of genes p53, APC and DCC together with mutational activation of k-ras oncogen, and in P-ADC, the inactivation of suppressor genes p53, p16 and DPC4 along with mutational activation of k-ras oncogen. P-ADC is the one showing a more characteristic and exclusive genetic mark, followed by CR-ADC. Finally, the histogenetic correlation in the tumorigenic sequence is more evident in CR-ADC, followed by P-ADC. The complex biologic reality of G-ADC makes it more difficult to draw its genetic profile and its histogenetic correlation. In order to understand better the arguments of this work, the authors comment on the genetic-molecular basis governing the life and death of normal somatic cells and the biologic profile of the groups of genes mainly involved in tumorigenesis.
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PMID:[Genetic abnormalities of digestive tract adenocarcinomas and correlation with the histologic sequence of their development]. 1867 2


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