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 investigated the clinical implications of allelic deletions at three common sites of loss of heterozygosity (LOH) in regions 5q21, 11p15.5, and 11p13 in 86 patients with non-small cell lung cancer (NSCLC). We performed a PCR-based microsatellite polymorphism assay for detection of LOH. The microsatellite markers used were D5S82 (proximal to the APC gene), MCC (within the MCC gene), D11S904 (11p13), HRAS (within the H-ras gene), and D11S860 (11p15.5). Of the 68 informative cases at 5q21 loci, LOH was found in 14 cases (20%), whereas LOH frequency in 11p15.5 and 11p13 was 31% (19 of 61 informative cases) and 19% (12 of 63 informative cases), respectively. There was a significant correlation between 5q21 LOH and mediastinal lymph node involvement (P = 0.03). However, no differences were observed in median survival times (26 months in patients with 5q21 LOH versus 37 months in the remainder; P = 0.33) nor in patients with 11p LOH (38 months versus 32 months, respectively; P = 0.72). Cox's proportional hazards model predicted that stage was the only independent poor prognostic marker in the entire cohort of NSCLC patients. Thus, the present study revealed two important abnormalities, LOH at chromosome 5q21 and LOH at chromosome 11p, both implied in NSCLC development.
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PMID:Microsatellite alterations at 5q21, 11p13, and 11p15.5 do not predict survival in non-small cell lung cancer. 981 4

The 11p15.5 region is associated with a broad range of diseases, including childhood acute myeloid leukemia; non-small cell lung carcinoma; arthrogryposis multiplex congenita, distal type 2B; and bladder cancer. Since targets for these diseases are unknown, we have constructed a physical map consisting of BAC and PAC clones spanning the region from the HRAS1 gene to the cluster of mucin genes on 11p15.5. The contig spans approximately 500 kb and includes 13 genes (9 novel), 9 STSs (5 novel), and 1 SNP and builds upon a published physical map spanning the region from the telomere to the HRAS gene. In addition, we expand the mucin gene cluster located on 11p15.5 to include a novel mucin-like gene (MUCDHL) located less than 250 kb telomeric to MUC6. The identification of potential disease genes within an organizational and evolutionary context provides valuable clues to function and as such will benefit our understanding of this region of the genome.
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PMID:Characterization of a 500-kb contig spanning the region between c-Ha-Ras and MUC2 on chromosome 11p15.5. 1103 Nov 2

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

Cancer is a complex disease that involves the accumulation of both genetic and epigenetic alterations of numerous genes. Data in the Genetic Alterations in Cancer database for gene mutations and allelic loss [loss of heterozygosity (LOH)] in human tumors (e.g. lung, oral, esophagus, stomach and colon/rectum) were reviewed. Results for the genes and pathways implicated in tumor development at these sites are presented. Mutation incidence, spectra and codon specificity are described for lung, larynx and oral tumors. LOH occurred more frequently than gene mutations in tumors from all sites examined. The cell cycle gene, TP53 (all sites), and cell signaling gene, APC (colorectal and gastric cancers), were the only genes with similar incidences of LOH and mutation. Alterations of one or more cell cycle and cell signaling genes were reported for tumors from each site. Site-specific activation was apparent in the cell signaling mitogen-activated protein kinase oncogenes (KRAS in lung, HRAS in oral cancers and BRAF in esophageal and colorectal cancers). Analysis of genetic changes in lung tumors showed that the incidence of mutations in the TP53 and KRAS genes and the incidence of LOH in the FHIT gene were significantly greater in smokers versus non-smokers (P < 0.01). In lung and oral cancers, the TP53 GC --> TA transversion frequency increased with tobacco smoke exposure (P < 0.05). Furthermore, the TP53 mutational hot spots for lung and laryngeal cancers from smokers included codons 157, 245 and 273, whereas for oral tumors included codons 280 and 281.
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PMID:Genetic pathways and mutation profiles of human cancers: site- and exposure-specific patterns. 1769 65

The colorectal cancer paradigm explains how genetic and histological changes lead normal epithelial cell to transform into pre-malignant adenomas then progress to malignant carcinomas. Using the Genetic Alterations in Cancer Knowledge System intragenic allele loss and gene mutation data from approximately 9000 colorectal tumors were compared to the model of colorectal tumor development. The distribution of mutations along the TP53 codons as a function of tumorigenesis also was analyzed. Alterations of APC, KRAS and TP53 were observed in a higher percentage of adenocarcinomas compared to adenomas (P<0.05) indicating that the alterations accumulated with malignancy. Alterations in BRAF, CTNNB, HRAS and NRAS were infrequent regardless of morphology. Differences were observed in the distribution of TP53 mutations with tumorigenesis. Mutations (single base substitutions) occurred most frequently at codons 175 and 273 in both tumor types; however, in adenocarcinomas the mutation incidence at codon 248 was approximately three times that reported in adenomas. It is proposed that the higher incidence of mutation at codon 248 is a later event in colorectal tumorigenesis that occurs as the tumors become malignant.
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PMID:Genetic pathways to colorectal cancer. 1957 32

Hepatocellular carcinoma (HCC) is the fifth most common cancer in India, and hepatitis B virus and hepatitis C virus infections are major risk factors. DNA methylation alterations have been linked to various carcinomas in different populations. Aberrant CpG island methylation of genes has been recognized in HCC, information is limited for hepatitis virus-related hepatocarcinogenesis. HCC risk has not previously been associated with gene-specific DNA methylation in India. Promoter region methylation of a panel of six tumor suppressor genes (CDKN2A, CDKN2B, CDH1, GSTP1, SOCS1, and APC) and three oncogenes (MYC, HRAS, and KRAS) was determined by methylation-specific PCR among 23 HCC samples and 20 control hepatitis samples. CDKN2B methylation frequency in HCC was double that for hepatitis, and methylation allele density of APC, GSTP1, and CDKN2B increased 2.2-, 2.3-, and 7.6-fold, respectively. Epigenetic silencing of tumor suppressor genes starts during viral infection and progresses toward HCC with the chronicity of the disease. Findings of altered methylation status support involvement of these tumor suppressor genes in HCC. MYC showed decreased methylation in HCC, relative to hepatitis. These observations on DNA methylation suggest the involvement of CDKN2B, SOCS1, CDH1, GSTP1, and MYC in pathogenesis of HCC in India and implicate altered DNA methylation in the molecular pathogenesis.
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PMID:Methylation profiling of tumor suppressor genes and oncogenes in hepatitis virus-related hepatocellular carcinoma in northern India. 1996 10

The bladder cancer genome harbors numerous oncogenic mutations and aberrantly methylated gene promoters. The aim of our study was to generate a profile of these alterations and investigate their use as biomarkers in urine sediments for noninvasive detection of bladder cancer. We systematically screened FGFR3, PIK3CA, TP53, HRAS, NRAS and KRAS for mutations and quantitatively assessed the methylation status of APC, ARF, DBC1, INK4A, RARB, RASSF1A, SFRP1, SFRP2, SFRP4, SFRP5 and WIF1 in a prospective series of tumor biopsies (N = 105) and urine samples (N = 113) from 118 bladder tumor patients. We also analyzed urine samples from 33 patients with noncancerous urinary lesions. A total of 95 oncogenic mutations and 189 hypermethylation events were detected in the 105 tumor biopsies. The total panel of markers provided a sensitivity of 93%, whereas mutation and methylation markers alone provided sensitivities of 72% and 70%, respectively. In urine samples, the sensitivity was 70% for all markers, 50% for mutation markers and 52% for methylation markers. FGFR3 mutations occurred more frequently in tumors with no methylation events than in tumors with one or more methylation events (78% vs. 33%; p < 0.0001). FGFR3 mutation in combination with three methylation markers (APC, RASSF1A and SFRP2) provided a sensitivity of 90% in tumors and 62% in urine with 100% specificity. These results suggest an inverse correlation between FGFR3 mutations and hypermethylation events, which may be used to improve noninvasive, DNA-based detection of bladder cancer.
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PMID:Integrated genetic and epigenetic analysis of bladder cancer reveals an additive diagnostic value of FGFR3 mutations and hypermethylation events. 2082 3

For most cases of colorectal cancer that arise without a family history of the disease, it is proposed that an appreciable heritable component of predisposition is the result of contributions from many loci. Although progress has been made in identifying single nucleotide variants associated with colorectal cancer risk, the involvement of low-penetrance copy number variants is relatively unexplored. We have used multiplex amplifiable probe hybridization (MAPH) in a fourfold multiplex (QuadMAPH), positioned at an average resolution of one probe per 2 kb, to screen a total of 1.56 Mb of genomic DNA for copy number variants around the genes APC, AXIN1, BRCA1, BRCA2, CTNNB1, HRAS, MLH1, MSH2, and TP53. Two deletion events were detected, one upstream of MLH1 in a control individual and the other in APC in a colorectal cancer patient, but these do not seem to correspond to copy number polymorphisms with measurably high population frequencies. In summary, by means of our QuadMAPH assay, copy number measurement data were of sufficient resolution and accuracy to detect any copy number variants with high probability. However, this study has demonstrated a very low incidence of deletion and duplication variants within intronic and flanking regions of these nine genes, in both control individuals and colorectal cancer patients.
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PMID:Screening for common copy-number variants in cancer genes. 2115 52

Endometriosis displays some features that resemble malignant processes, including invasive growth, resistance to apoptosis and distant implantation. The objective of this study was to investigate whether gene alterations that are frequent in endometrial and/or ovarian cancers contribute to the pathogenesis of endometriosis. Biopsies were obtained from ectopic endometriosis lesions from 23 patients with revised American Fertility Score stage 1 (n= 1), 2 (n= 10), 3 (n= 11) or 4 (n= 1) endometriosis. Six genes (APC, CDKN2A, PYCARD, RARB, RASSF1 and ESR1) were analyzed for promoter hypermethylation using methylation-specific melting curve analysis, and 9 genes (BRAF, HRAS, NRAS, CTNNB1, CDK4, FGFR3, PIK3CA, TP53 and PTEN) were analyzed for mutations using denaturing gradient gel electrophoresis and direct sequencing. An oncogenic mutation in KRAS (c.34G > T; p.G12C) was detected in a single lesion. No gene alterations were found in the remaining samples. Our data suggest that genetic and epigenetic events contributing to endometrial and ovarian cancers are rare in endometriosis. However, other proto-oncogenes and tumor suppressor genes should be tested for alterations in order to identify the molecular basis of the susceptibility of endometriosis to malignant transformation.
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PMID:Oncogenic events associated with endometrial and ovarian cancers are rare in endometriosis. 2212 88

Extramammary Paget's disease (EMPD) is a rare cutaneous malignant neoplasm. The genetic alterations underlying its pathogenesis have less been described. Therefore, we analyzed the possible mutations in the KRAS, HRAS, NRAS, BRAF, ARAF, RAF1, PIK3CA, AKT1, CTNNB1 and APC genes as well as methylation and expression of CDH1 in 144 EMPD cases and 42 matched normal skin tissues. A distinct mutation profile was identified in EMPDs with 27 (19%) cases mutant for RAS and RAF genes and 50 (35%) cases harboring oncogenic mutations in PIK3CA and AKT1. Moreover, a mutually exclusive pattern was observed in the genetic variants in these two signaling pathways. No mutation was detected in CTNNB1 and APC genes. High prevalence of low expression and hypermethylation of CDH1 gene was detected in 33 and 48% of the EMPD cases, respectively. Furthermore, PIK3CA and AKT1 mutations were significantly correlated with CDH1 hypermethylation which could explain why the majority of EMPD cases with mutant PIK3CA and AKT1 were invasive. Our study demonstrates that genetic variants associated with constitutive activation of RAS/RAF and PI3K/AKT pathways are involved in the pathogenesis of EMPD. This may represent novel therapeutic targets for this skin cancer.
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PMID:Oncogenic mutations in extramammary Paget's disease and their clinical relevance. 2282 Dec 11


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