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)

We have previously reported successful trans-complementation of defective Kunjin virus genomic RNAs with a range of large lethal deletions in the nonstructural genes NS1, NS3, and NS5 (A. A. Khromykh et al., J. Virol. 74:3253-3263, 2000). In this study we have mapped further the minimal region in the NS5 gene essential for efficient trans-complementation of genome-length RNAs in repBHK cells to the first 316 of the 905 codons. To allow amplification and easy detection of complemented defective RNAs with deletions apparently affecting virus assembly, we have developed a dual replicon complementation system. In this system defective replicon RNAs with a deletion(s) in the nonstructural genes also encoded the puromycin resistance gene (PAC gene) and the reporter gene for beta-galactosidase (beta-Gal). Complementation of these defective replicon RNAs in repBHK cells resulted in expression of PAC and beta-Gal which allowed establishment of cell lines stably producing replicating defective RNAs by selection with puromycin and comparison of replication efficiencies of complemented defective RNAs by beta-Gal assay. Using this system we demonstrated that deletions in the C-terminal 434 codons of NS3 (codons 178 to 611) were complemented for RNA replication, while any deletions in the first 178 codons were not. None of the genome-length RNAs containing deletions in NS3 shown to be complementable for RNA replication produced secreted defective viruses during complementation in repBHK cells. In contrast, structural proteins produced from these complemented defective RNAs were able to package helper replicon RNA. The results define minimal regions in the NS3 and NS5 genes essential for the formation of complementable replication complex and show a requirement of NS3 in cis for virus assembly.
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PMID:Complementation analysis of the flavivirus Kunjin NS3 and NS5 proteins defines the minimal regions essential for formation of a replication complex and shows a requirement of NS3 in cis for virus assembly. 1236 19

The genomic alterations in preneoplastic lesions are summarized in this review. 3p and 9p in the lung, 9p in the bladder, 8p in the prostata, 19q and 1p in oligodendroglioma, and 22q in meningioma were reported to be deleted. Somatic mutation of p53 was found in preneoplastic lesions of the esophagus, stomach, colon, thyroid, and astrocytoma. Adenoma-carcinoma sequence (Apc, ras, p53 gene alterations) in colon, LKB1 gene in Peutz-Jeghers syndrome, Smad4 in juvenile polyposis, hMSH2, hMLH1, PMS1, PMS2 genes in HNPCC, VHL gene in kidney, WT1 in Wilms tumor, RB gene in retinoblastoma, and ret gene in MEN were reportedly altered in preneoplastic lesions involved in hereditary tumors. Cervical dysplasia and papilloma of the head and neck infected by human papilloma virus and liver infected by B-type hepatitis virus are also precancerous. Genomic instability, APC gene alteration, point mutation of K-ras in preneoplastic lesions of stomach and K-ras and p16 alterations in metaplasia of pancreas were also found. Advances in research on genomic alterations in preneoplastic lesions will contribute to prevention and early detection of cancer.
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PMID:[Genomic alterations in preneoplastic lesions]. 1250 66

Stage I non-small cell carcinoma (NSCLC) of the lung is typically treated with surgery alone, but with a 30 to 40% recurrence rate. Prognostic factors to stratify these patients into high- and low-risk groups would be of significant clinical value, but published data are conflicting. We studied 39 Stage I NSCLC treated with resection alone, followed for a minimum of 5 years, and divided into recurrent (RC) and non-recurrent (NRC) groups (n = 12 and 27, respectively). Allelic imbalance (loss of heterozygosity, LOH) involving genomic regions containing L-myc (1p32), hOGG1 (3p26), APC/MCC (5q21), c-fms (5q33.3), p53 (17p13), and DCC (18q21), and point mutational change in K-ras-2 (12p12) were studied by PCR-based microsatellite analysis and DNA sequencing. Mutations in k-ras-2 were seen in 25% and 19% of RC and NRC tumors, respectively, most frequently in adenocarcinomas. LOH in the RC and NRC respectively were 50% and 37% for L-myc, 60% and 33% for hOGG1, 60% and 50% for APC, 38% and 35% for c-fms, 78% and 75% for p53, and 17% and 45% for DCC. No statistical significance was seen comparing any of the allelic alterations with recurrence. LOH for hOGG1 and L-myc were more commonly seen in squamous cell carcinomas. Stage I NSCLC are genetically heterogeneous with respect to mutation acquisition. The approach of investigating a panel of genes for alterations can be applied to any given tumor type, and provides information on patterns of mutations/LOH that can help us better understand the molecular biology of tumorigenesis.
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PMID:Widespread molecular alterations present in stage I non-small cell lung carcinoma fail to predict tumor recurrence. 1252 10

Tumour cell lines are commonly used in colorectal cancer (CRC) research, including studies designed to assess methylation defects. Although many of the known genetic aberrations in CRC cell lines have been comprehensively described, no studies have been performed on their methylation status. In this study, 30 commonly used CRC cell lines as well as seven primary tumours from individuals with hereditary nonpolyposis colorectal cancer (HNPCC) were assessed for methylation at six CpG islands known to be hypermethylated in colorectal cancer: hMLH1, p16, methylated in tumour (MINT-)-1, -2, -12 and -31. The cell lines were also assessed for microsatellite instability (MSI), ploidy status, hMLH1 expression, and mutations in APC and Ki-ras. Methylation was frequently observed at all examined loci in most cell lines, and no differences were observed between germline-derived and sporadic cell lines. Methylation was found at MINT 1 in 63%, MINT 2 in 57%, MINT 12 in 71%, MINT 31 in 53%, p16 in 71%, and hMLH1 in 30% of cell lines. Overall only one cell line, SW1417, did not show methylation at any locus. Methylation was found with equal frequency in MSI and chromosomally unstable lines. MSI was over-represented in the cell lines relative to sporadic CRC, being detected in 47% of cell lines. The rate of codon 13 Ki-ras mutations was also over three times that expected from in vivo studies. We conclude that CpG island hypermethylation, whether acquired in vivo or in culture, is a ubiquitous phenomenon in CRC cell lines. We suggest that CRC cell lines may be only representative of a small subset of real tumours, and this should be taken into account in the use of CRC cell lines for epigenetic studies.
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PMID:CpG island methylation is a common finding in colorectal cancer cell lines. 1256 85

Unlike other types of cancer, there are several options for screening for colorectal cancer (CRC). The most extensively examined method, faecal occult blood testing (FOBT), has been shown, in three large randomized trials, to reduce mortality from CRC by up to 20% if offered biennally and possibly more if offered every year. Recently published data from the US trial suggest that CRC incidence rates are also reduced by up to 20%, but only after 18 years. In this study, the number of positive slides was associated with the positive predictive value both for CRC and adenomas larger than 1 cm, suggesting that the reduction in CRC incidence was caused by the identification and removal of large adenomas. In this respect, this study supports the concept that removing adenomas prevents CRC. More efficient methods of detecting adenomas include the use of colonoscopy or flexible sigmoidoscopy (FS). Considerable evidence exists from case-control and uncontrolled cohort studies to suggest that endoscopic screening by sigmoidoscopy reduces incidence of distal colorectal cancer. However, in the absence of evidence from a randomized trial, several countries have been reluctant to introduce endoscopic screening. Three trialsare currently in progress (in the UK, Italy and the US) to address this issue. Two of these trials are examining the hypothesis that a single FS screen at around age 55-64 might be a cost-effective and acceptable method for reducing CRC incidence rates. Recruitment and screening are now complete in both studies and the first analysis of results on incidence rates is expected in 2004. Colonoscopy screening at 10-year intervals has recently been endorsed in the US on the basis that the reductions in incidence observed with distal CRC screening can be extrapolated to the proximal colon. However, data are lacking and a pilot study for a trial of the acceptability and efficacy of colonoscopy screening is in progress in the US. It has also been suggested that FOBT testing should be used to detect proximal CRC missed by sigmoidoscopy screening, but the small amount of published data suggest that supplementing FS with FOBT offers very little advantage over FS alone. Other forms of CRC screening are under investigation and represent exciting options for the future. Extraction of DNA from stool is now feasible and a number of research groups have shown high sensitivity for CRC using a panel of DNA markers including mutations in k-ras, APC, p53 and BAT26. Data so far indicate that, with the exception of k-ras, these markers are highly specific and therefore represent a significant improvement over FOBT. Whether these tests will replace or supplement existing methods of screening has yet to be determined. It has been suggested that BAT26, which is a marker of microsatellite instability, a feature of proximal sporadic CRC, might be a useful adjunct to sigmoidoscopy screening. Others have suggested that a test for occult blood should be included with the DNA markers to further increase sensitivity. It is not yet known how sensitive these markers are for adenomas--it is only by detecting adenomas that CRC incidence rates can be reduced. A final exciting new option for screening is virtual colonoscopy (VC), which by screening out people without neoplasia allows colonoscopy to be reserved for patients requiring a therapeutic intervention. The sensitivity of VC for large adenomas and CRC appears to be high, although results vary by centre and there is a steep learning curve. Sensitivity for small adenomas is low, but perhaps it is less essential to find such lesions. Some groups have suggested that virtual colonoscopy might be a useful option for investigating patients who test positive with stool-based screening tests. Whichever CRC screening method is finally chosen (and there is no reason why several methods should not ultimately be available), high quality endoscopy resources will always be required to investigate and treat neoplastic lesions detected.
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PMID:Options for screening for colorectal cancer. 1279 74

The I1307K APC germline mutation is associated with an increased risk to colorectal cancer (CRC). Whether and to what extent the somatic features and the molecular pathways of cancer development in mutation carriers differ from colorectal cancer in noncarriers remains unknown. To gain insight into this issue, 52 Israeli patients with CRC, 24 of whom were I1307K APC mutation carriers, were analyzed. The expression pattern of genes known to be involved in the pathogenesis of sporadic CRC was assessed immunohistochemically: E-cadherin, beta-catenin, deleted in colon cancer (DCC), and p53. In addition, tumors were genotyped for somatic activating mutations in Ki-ras oncogene. Mutation carriers and noncarriers were comparable in age at diagnosis (64.3 +/- 10.1 years for carriers and 60.8 +/- 14.1 years for noncarriers), tumor location in the colon, and disease stages. Tumors of I1307K mutation carriers displayed positive p53 immunostaining and loss of beta-catenin, E-cadherin, and DCC expression more often compared with noncarriers, although none of these differences reached statistical significance. Mutation frequencies in the Ki-ras gene were similar in both groups. In conclusion, the molecular pathways in CRC in I1307K APC mutation carriers are seemingly similar to those of sporadic cases, but a larger study is clearly needed.
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PMID:Immunohistochemical analyses of colon cancer in I1307K APC mutation carriers compared with noncarriers. 1282 69

BRAF, a serine/threonine kinase of the RAF family, is a downstream transducer of the RAS-regulated MAPK pathway and signals upstream of MEK1/2 kinases. Recently, activating mutations within BRAF have been reported in a high percentage of melanomas and colorectal carcinomas and shown to have oncogenic capabilities. Further, their association to mismatch-repair-deficient tumors has suggested the involvement of the RAS/RAF pathway in the tumorigenesis of microsatellite-unstable colon cancers, and that RAS and RAF mutations are alternative genetic events. We determined whether colorectal mismatch-repair-deficient tumors with BRAF mutations show a specific genotype when compared with tumors with wild-type BRAF, and whether they can be associated with a particular clinicopathological feature. Here, we report a striking association of BRAF, but not of APC, KRAS2, AXIN2, and TP53 mutations, with proximal mismatch-repair-deficient colon tumors and MLH1 hypermethylation. Our results support the hypothesis that proximal and distal colorectal tumors with mismatch repair deficiency harbor different genetic alterations, and we suggest that the involvement of the RAS/RAF pathway in colorectal tumorigenesis is differentially modulated according to tumor location and MLH1 inactivation.
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PMID:Activated BRAF targets proximal colon tumors with mismatch repair deficiency and MLH1 inactivation. 1469 93

The detection and removal of advanced colonic polyps (ACPs) can help prevent the development of colorectal cancer. A set of DNA mutations known to be associated with colorectal carcinoma was tested against resected ACPs to determine the set s potential utility as a marker panel for ACPs. A sensitive mutation marker panel could be used by stool-based assays that look for mutated human DNA to detect the presence of ACPs. DNA from 32 ACPs = 1.0 cm in diameter was amplified and tested for 19 colorectal cancer associated DNA mutations and for deletions in BAT-26 (microsatellite instability). One or more mutations were identified by microsequencing in 28 of the 32 ACPs (88%). Mutations were identified in k-ras (59%), APC (33%), and p53 (22%). BAT-26 mutation, a marker for microsatellite instability, was not identified. Stool DNA based assays that can identify these mutations may significantly increase the identification of patients with potentially premalignant ACPs for evaluation and treatment by colonoscopy.
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PMID:Gene mutations in advanced colonic polyps: potential marker selection for stool-based mutated human DNA assays for colon cancer screening. 1470 78

Biallelic germ-line variants of the 8-hydroxyguanine repair gene MYH have been associated with multiple colorectal adenomas that display somatic G:C-->T:A transversions in APC. However, the effect of single germ-line variants has not been widely studied. To examine the relationship between monoallelic MYH variants and susceptibility to sporadic colorectal cancer (CRC), 92 cases of sporadic CRC, 19 cases of familial CRC not meeting the Bethesda guidelines, 17 cases with multiple adenomas, and 53 normal blood donors were screened for 8 potentially pathogenic germ-line MYH variants. Loss of heterozygosity (LOH) at 1p adjacent to the MYH locus, microsatellite instability (MSI) status, and somatic mutations in KRAS2 and APC were analyzed in sporadic cancers. Neither homozygote nor compound heterozygote MYH variants were observed in the germ-line of any subjects with sporadic CRC. There was no difference in the incidence of monoallelic variants between this group (20 of 92, 22%) and cancer-free controls (14 of 53, 26%). However, the presence of monoallelic germ-line MYH variants was negatively associated with an MSI-high (MSI-H) tumor phenotype, with an incidence of only 1 of 23 (4%) MSI-H CRCs as contrasted with 19 of 69 (28%) non-MSI-H (P=0.02). Further, 4 of 5 tumors with 1p LOH contained monoallelic MYH variants compared with 15 of 53 without 1p LOH (P=0.04) and the normal population (P=0.03). The presence of G:C-->T:A transversions in KRAS2 or APC was significantly more common in single MYH variant tumors (9 of 12) than in MYH wild-type tumors (11 of 33; P=0.02). These results suggest that single germ-line variants of MYH may influence genetic pathways in CRC.
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PMID:Role of inherited defects of MYH in the development of sporadic colorectal cancer. 1503 62

Colorectal cancer (CRC) is one of the most common forms of cancer and the second leading cause of death in Poland. Most cases of CRC are sporadic but a small percentage occurs in heritable syndromes such as dominant autosomal adenomatous and hamartomatous polyposis syndromes and hereditary nonpolyposis colorectal cancers. In a majority of cases CRCs are thought to develop in a step wise progression from normal epithelium through polyp form to carcinoma. Many genetic changes are observed in this process like inactivation of the tumor suppressor genes as well as the activation of specific oncogenes. Molecular biological studies have shown mutations of p53, Apc, k-ras and/or changes in proteins like APC and DNA microsatellite instability or loss of heterozygosity. For several years now great progress in this field and new concepts of screening strategies and therapeutic options have been made (gene therapy).
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PMID:[Genetic aspects of colorectal carcinogenesis]. 1518 54


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