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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Carcinogenesis 2007 Sep
PMID:Genetic pathways and mutation profiles of human cancers: site- and exposure-specific patterns. 1769 65

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate expression of many genes. Recent studies suggest roles of miRNAs in carcinogenesis. We and others have shown that expression profiles of miRNAs are different in lung cancer vs. normal lung, although the significance of this aberrant expression is poorly understood. Among the reported down-regulated miRNAs in lung cancer, the miRNA (miR)-29 family (29a, 29b, and 29c) has intriguing complementarities to the 3'-UTRs of DNA methyltransferase (DNMT)3A and -3B (de novo methyltransferases), two key enzymes involved in DNA methylation, that are frequently up-regulated in lung cancer and associated with poor prognosis. We investigated whether miR-29s could target DNMT3A and -B and whether restoration of miR-29s could normalize aberrant patterns of methylation in non-small-cell lung cancer. Here we show that expression of miR-29s is inversely correlated to DNMT3A and -3B in lung cancer tissues, and that miR-29s directly target both DNMT3A and -3B. The enforced expression of miR-29s in lung cancer cell lines restores normal patterns of DNA methylation, induces reexpression of methylation-silenced tumor suppressor genes, such as FHIT and WWOX, and inhibits tumorigenicity in vitro and in vivo. These findings support a role of miR-29s in epigenetic normalization of NSCLC, providing a rationale for the development of miRNA-based strategies for the treatment of lung cancer.
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PMID:MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. 1789 Mar 17

Nickel(II) compounds are carcinogenic metals which induce genotoxicity and oxidative stress through the generation of reactive oxygen species. In search of new molecular pathways toward understanding the molecular mechanism of nickel(II)-induced carcinogensis, we performed mRNA differential display analysis using total RNA extracted from nickel(II) acetate-treated normal rat kidney cells (NRK-52E). Cells were exposed for 2 months to 160 and 240 microM nickel(II) concentrations. cDNAs corresponding to mRNAs for which expression levels were altered by nickel(II) were isolated, sequenced, and followed by a GenBank Blast homology search. Specificity of differential expression of cDNAs was determined by RT-PCR. Two of them (SH3BGRL3 and FHIT) were down-regulated and one (metallothionein) was up-regulated by nickel(II) treatment. The expression of these mRNAs were nickel(II) concentration-dependent. Overall, although the fundamental questions related to function of these genes in nickel(II)-mediated carcinogenicity are not answered, our study suggests that they can be interesting candidates for studies of molecular mechanisms of nickel(II) carcinogenesis.
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PMID:Differential gene expression in nickel(II)-treated normal rat kidney cells. 1797 98

Copy number changes and DNA methylation alterations are crucial to gene regulation in mammals. Recently, a number of microarray studies have been based on copy number and DNA methylation alterations in order to find clinical biomarkers of carcinogenesis. In this study, we attempted to combine profiles of copy number and methylation patterns in four human cancer cell lines using BAC microarray-based approaches and we detected several clinically important genes which showed genetic and epigenetic relationships. Within the clones analyzed, many contained cancer-related genes involved in cell cycle regulation, cell division, signal transduction, tumor necrosis, cell differentiation, and cell proliferation. One clone included the FHIT gene, a well-known tumor suppressor gene involved in various human cancers. Our combined profiling techniques may provide a method by which to find new clinicopathologic cancer biomarkers, and support the idea that systematic characterization of the genetic and epigenetic events in cancers may rapidly become a reality.
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PMID:Genome-wide combination profiling of copy number and methylation offers an approach for deciphering misregulation and development in cancer cells. 1799 35

To clarify the roles of FHIT (fragile histidine triad) and PTEN (phosphatase and tensin homology deleted from human chromosome 10) expression in the genesis and progression of gastric cancers, we examined expression of FHIT and PTEN on tissue microarray containing gastric normal mucosa (n=49), adenoma (n=49), noncancerous mucosa adjacent to carcinoma (n=84) and carcinoma (n=249) by immunohistochemistry. Their expression was compared with clinicopathologic parameters of tumors, including expression of p53 and cysteine protease protein 32 as well as survival time of patients with carcinoma. The results showed expression of FHIT and PTEN were lower in gastric carcinoma than those in normal mucosa, noncancerous mucosa adjacent to carcinoma and adenoma of the stomach (P<0.05). FHIT and PTEN expression showed a significantly negative association with depth of invasion, lymphatic invasion, and lymph node metastasis, liver metastasis, and Union Internationale Contre le Cancer staging of gastric carcinoma (P<0.05). Intestinal-type gastric carcinomas highly expressed FHIT and PTEN protein, compared with diffuse-type ones (P<0.05). Expression of FHIT and PTEN were positively related with expression of p53 and cysteine protease protein 32 in gastric carcinoma (P<0.05), as well as favorable prognosis of the patients with the tumors (P<0.05). There was positive relationship between FHIT and PTEN expression in gastric carcinoma (P<0.05). It was suggested that down-regulated expression of FHIT and PTEN contributed to gastric carcinogenesis possibly by involving in the imbalance between apoptosis and proliferation of cells. Their altered expression underlay the molecular basis of invasion, metastasis, differentiation of gastric carcinoma.
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PMID:Low expression of FHIT and PTEN correlates with malignancy of gastric carcinomas: tissue-array findings. 1809 87

Early in tumorigenesis, a DNA damage-response network is activated in preneoplastic cells that delays or prevents cancer. Activation of the Chk2 G(2)/M checkpoint kinase and loss of fragile histidine triad (Fhit) tumor suppressor expression increase cellular susceptibility to DNA-damaging 'oncogenic' stressors, particularly in precursor or precancerous lesions. To understand the mechanism of oral carcinogenesis, we assessed the association between phosphorylated Chk2 (pChk2) and Fhit expression in oral squamous cell carcinoma. Loss of Fhit expression was an early event during oral carcinogenesis, whereas a decrease in the number of pChk2-positive cells was associated with tumor progression. Although tyrosine 114 is known to be essential to Fhit's tumor-suppressing activity, both wild-type and tyrosine 114 mutant Fhit increased the population of subG(1) DNA-containing HSC-3 OSCC cells with elevated pChk2 levels. In particular, when cells were exposed to ionizing radiation, pChk2 levels were upregulated dramatically, as were those of its downstream target Cdc25C. Knockdown of Fhit with FHIT small interfering RNA diminished the ionizing radiation-induced Chk2 phosphorylation in HEK293 cells. Furthermore, Fhit-deficient mice demonstrated a decrease in the number of pChk2-positive cells not only in dysplastic lesions but also in N-nitrosobenzylamine-induced papilloma of the forestomach, suggesting that lack of Fhit expression and the resultant defects of the ataxia telangiectasia mutated-Chk2 pathway can cause a difference in the incidence of N-nitrosobenzylamine-induced forestomach lesions. These findings suggest that Fhit plays a key role in the regulation of the ataxia telangiectasia mutated-Chk2 DNA damage response during oral carcinogenesis.
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PMID:Restoration of fragile histidine triad expression restores Chk2 activity in response to ionizing radiation in oral squamous cell carcinoma cells. 1816 29

DNA methylation is an important mechanism for gene silence. The purpose of this study was to investigate aberrant promoter methylation of the p16 and FHIT genes in tissues and plasma and loss of protein expression in esophageal precancerous conditions (EPC) and esophageal squamous cell carcinoma (ESCC) of high-risk area. Methylation-specific PCR(MSP) was employed to examine the DNA methylation in the plasma and tissues of 95 patients of EPC, ESCC and 10 chronic esophagitis (CE). Loss of protein expression of p16 and FHIT was detected immunohistochemically. In total 95 lesion tissues of EPC and ESCC, p16 methylation was found in 53 (55.79%) cases, and 41 of 53 (77.36%) cases were demonstrated deletion of the p16 protein immunohistochemically. FHIT methylation was found in 49 (51.58%) cases, and 40 of 49 (81.63%) were demonstrated deletion of the FHIT protein. Only 1 (10%) case of 10 CE p16 methylation was found in the tissues. In the plasma of total 105 samples, 2 of 23 high grade intraepithelial neoplasia (HGIN) and 12 of 37 ESCC were detected p16 methylation, and 2 of 23 HGIN and 14 of 37 ESCC were detected FHIT methylation. These results indicate that p16 and FHIT methylation may be one of the earliest events and an important mechanism for gene silencing in esophageal squamous cell carcinogenesis. This study may be helpful for screening the candidate molecular markers for early diagnosis of ESCC in high-risk area.
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PMID:DNA methylation and loss of protein expression in esophageal squamous cell carcinogenesis of high-risk area. 1836 57

Genetic aberrations are crucial in renal tumor progression. In this study, we describe loss of heterozygosity (LOH) and DNA-copy number abnormalities in clear cell renal cell carcinoma (cc-RCC) discovered by genome-wide single nucleotide polymorphism (SNP) arrays. Genomic DNA from tumor and normal tissue of 22 human cc-RCCs was analyzed on the Affymetrix GeneChip Human Mapping 10K Array. The array data were validated by quantitative polymerase chain reaction and immunohistochemistry. Reduced DNA copy numbers were detected on chromosomal arm 3p in 91%, on chromosome 9 in 32%, and on chromosomal arm 14q in 36% of the tumors. Gains were detected on chromosomal arm 5q in 45% and on chromosome 7 in 32% of the tumors. Copy number abnormalities were found not only in FHIT and VHL loci, known to be involved in renal carcinogenesis, but also in regions containing putative new tumor suppressor genes or oncogenes. In addition, microdeletions were detected on chromosomes 1 and 6 in genes with unknown impact on renal carcinogenesis. In validation experiments, abnormal protein expression of FOXP1 (on 3p) was found in 90% of tumors (concordance with SNP array data in 85%). As assessed by quantitative polymerase chain reaction, PARK2 and PACRG were down-regulated in 57% and 100%, respectively, and CSF1R was up-regulated in 69% of the cc-RCC cases (concordance with SNP array data in 57%, 33%, and 38%). Genome-wide SNP array analysis not only confirmed previously described large chromosomal aberrations but also detected novel microdeletions in genes potentially involved in tumor genesis of cc-RCC.
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PMID:Loss of heterozygosity and copy number abnormality in clear cell renal cell carcinoma discovered by high-density affymetrix 10K single nucleotide polymorphism mapping array. 1859 4

The European Early Lung Cancer (EUELC) project aims to determine if specific genetic alterations occurring in lung carcinogenesis are detectable in the respiratory epithelium. In order to pursue this objective, nonsmall cell lung cancer (NSCLC) patients with a very high risk of developing progressive lung cancer were recruited from 12 centres in eight European countries: France, Germany, southern Ireland, Italy, the Netherlands, Poland, Spain and the UK. In addition, NSCLC patients were followed up every 6 months for 36 months. A European Bronchial Tissue Bank was set up at the University of Liverpool (Liverpool, UK) to optimise the use of biological specimens. The molecular-pathological investigations were subdivided into specific work packages that were delivered by EUELC Partners. The work packages encompassed mutational analysis, genetic instability, methylation profiling, expression profiling utilising immunohistochemistry and chip-based technologies, as well as in-depth analysis of FHIT and RARbeta genes, the telomerase catalytic subunit hTERT and genotyping of susceptibility genes in specific pathways. The EUELC project engendered a tremendous collaborative effort, and it enabled the EUELC Partners to establish protocols for assessing molecular biomarkers in early lung cancer with the view to using such biomarkers for early diagnosis and as intermediate end-points in future chemopreventive programmes.
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PMID:EUELC project: a multi-centre, multipurpose study to investigate early stage NSCLC, and to establish a biobank for ongoing collaboration. 1994 14

A total of 176 genes homozygously deleted in human lung cancer were identified by DNA array-based whole genome scanning of 52 lung cancer cell lines and subsequent genomic PCR in 74 cell lines, including the 52 cell lines scanned. One or more exons of these genes were homozygously deleted in one (1%) to 20 (27%) cell lines. These genes included known tumor suppressor genes, e.g., CDKN2A/p16, RB1, and SMAD4, and candidate tumor suppressor genes whose hemizygous or homozygous deletions were reported in several types of human cancers, such as FHIT, KEAP1, and LRP1B/LRP-DIP. CDKN2A/p16 and p14ARF located in 9p21 were most frequently deleted (20/74, 27%). The PTPRD gene was most frequently deleted (8/74, 11%) among genes mapping to regions other than 9p21. Somatic mutations, including a nonsense mutation, of the PTPRD gene were detected in 8/74 (11%) of cell lines and 4/95 (4%) of surgical specimens of lung cancer. Reduced PTPRD expression was observed in the majority (>80%) of cell lines and surgical specimens of lung cancer. Therefore, PTPRD is a candidate tumor suppressor gene in lung cancer. Microarray-based expression profiling of 19 lung cancer cell lines also indicated that some of the 176 genes, such as KANK and ADAMTS1, are preferentially inactivated by epigenetic alterations. Genetic/epigenetic as well as functional studies of these 176 genes will increase our understanding of molecular mechanisms behind lung carcinogenesis.
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PMID:A catalog of genes homozygously deleted in human lung cancer and the candidacy of PTPRD as a tumor suppressor gene. 2007 72


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