Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Differential gene methylation is observed in a variety of human malignancies. The study of the pattern of methylated genes helps to understand carcinogenesis and to identify potential marker tumor genes for clinical use. The differential methylated genes in undifferentiated nasopharyngeal carcinoma (NPC) of Chinese were studied by methylation-specific polymerase chain reaction (MSP). Methylation status of 11 tumor-associated genes (ARF, caspase-8, CDH1, CDKN2A, CDKN2B, MGMT, MLH1, RASSF1A, THBS1, TP73 and VHL) was studied in 30 primary undifferentiated NPC and paired peripheral blood of 12 patients. The methylation profile of NPC in order of frequency was CDH1 (50%), CDKN2B (50%), THBS1 (50%), RASSF1A (46%), MLH1 (40%), MGMT (28%), CDKN2A (23%), TP73 (20%), caspase-8 (7%), ARF (3%) and VHL (0%). Methylation of at least 1 gene was observed in 93% of primary NPC. Of the 12 patients with at least 1 methylated gene in the primary tumor, all 12 (100%) patients had at least 1 of the methylated gene promoter detectable in their peripheral blood. The results show high frequency of methylation in NPC and the potential of using methylation as peripheral blood tumor marker in screening NPC.
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PMID:Differential gene methylation in undifferentiated nasopharyngeal carcinoma. 1263 81

The CDKN2A tumor-suppressor gene in chromosome band 9p21 encoding CDKN2A (also known as p16, INK4A), a negative regulator of cyclin-dependent kinases, and p14(ARF1), an activator of TP53, is inactivated in many human cancers by point mutations, promoter hypermethylation, or deletions. Homozygous deletions predominate in certain cancer types (e.g., bladder cancers). To understand why deletions are unusually prevalent at this locus, deletions in bladder and renal cancer cell lines were mapped in detail and several deletion breakpoints cloned. Deletions were interstitial and encompassed 0.1 to >30 Mb. Most deletion breakpoints were located in or close to LINE-1 retrotransposon clusters. Therefore, deletions of CDKN2A may be facilitated by the presence of LINE-1 clusters that flank the locus. All cloned junctions were products of non-homologous recombination and consistently contained exact 2-bp microhomologies. Microhomologies are otherwise hallmarks of DNA double-strand break repair by non-homologous end joining, but the consistent size found at the CDKN2A deletion junctions is difficult to reconcile with the known properties of this process. Therefore, an unknown mechanism appears to be involved in the generation of CDKN2A deletions during carcinogenesis.
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PMID:Peculiar structure and location of 9p21 homozygous deletion breakpoints in human cancer cells. 1269 62

The present study was designed to investigate the potential relationship between CDKN2A (p16) gene hypermethylation, which has reported to be frequently observed in oral squamous cell carcinomas (OSCCs), and expression of human DNA methyltransferases (DNMTs: DNMT1, DNMT3A and DNMT3B). Twenty-five pairs of primary OSCCs and matched normal oral mucosa tissues were examined. The p16 gene was hypermethylated (48%) in the tumors showing significant down-regulation of both mRNA and protein expressions. A demethylation assay on 8 OSCC-derived cell lines was also performed by means of treatment with the demethylating agent, 5-aza-2'-deoxycytidine. Four of 5 cell lines showing down-regulation of the p16 gene, revealed re-activation of gene expression after the treatment. In contrast, frequent over-expression of DNMT mRNA expression, also found in the expression of the proteins, was detected: DNMT1 at 72% and DNMT3A at 56%, and DNMT3B at 64%, respectively. However, we could not identify any statistical significance between p16-hypermethylation status in individual tumors and the expression of any of the three DNMTs. These data suggest that hypermethylation of the p16 gene and up-regulation of DNMTs are involved in oral carcinogenesis, but they may be through different mechanisms.
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PMID:Over-expression of DNA methyltransferases and CDKN2A gene methylation status in squamous cell carcinoma of the oral cavity. 1273 84

Promoter hypermethylation of the CDKN2A gene has been suspected to be involved in the carcinogenesis of colorectal cancers. However, the relations between CDKN2A hypermethylation and clinicopathological findings, and patient prognosis, remain inconclusive. We analyzed the CDKN2A methylation status in primary colorectal cancers using real-time methylation specific PCR (MethyLight) which enables quantitative measuring of the methylation level. CDKN2A promoter methylation was detectable in 55 (61.1%) of 90 tumor samples and the median level of the methylation was 0.187 (range 0.00-197.9). The methylation value of CDKN2A was correlated with certain clinicopathological findings, including tumor differentiation (p=0.018), and Dukes stage (p=0.016). In survival analysis, the CDKN2A methylation level was correlated with a poor prognosis of the patient with colorectal cancer for either all cases (p=0.014) or Dukes C (p=0.004) cases that were analyzed. These results suggest that CDKN2A methylation status is a prognostic factor in colorectal cancer and may be of use for the patient specific design of therapy.
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PMID:Hypermethylation of the CDKN2A gene in colorectal cancer is associated with shorter survival. 1279 48

Hypermethylation of cytosines in CpG-rich islands of the promoter regions of regulatory genes has been discovered as a common mechanism of gene silencing during carcinogenesis. We analysed 64 primary lung carcinomas for promoter methylation of the tumour suppressor genes (TSGs) p16 (p16(INK4a)/CDKN2A) and p14 (p14(ARF)) by methylation-specific PCR, in order to evaluate aberrant methylation as a potential biomarker for epigenetic alterations in tobacco-related lung cancer. Methylation of p16 was observed in 34% (22/64) of the lung tumours examined. In particular, p16 methylation occurred in nonsmall cell lung cancer (NSCLC) only, with 41 % (22/54) of the tumours being positive. The highest frequency was found in large cell carcinoma (5/7, 71%), followed by adenocarcinoma (9/25, 36%) and squamous cell carcinoma (7/21, 33%). Methylation of the p14 gene was less frequent in lung cancer (4/52, 8%). When association with tobacco smoking was analysed, 42% (21/50) of NSCLC from ever smokers exhibited p16 methylation. Interestingly, the analysis revealed a significantly higher risk of p16 methylation in former smokers as compared to current smokers [odds ratio (OR) 5.1; 95% confidence interval (CI) 1.3-22]. The difference was retained after adjustment for age (OR 3.7; 95% CI 0.9-17). The promoter methylation results were then combined with data on genetic alterations determined previously in the same set of tumours. This data similarly showed that p16 methylation in parallel with p53 gene mutation or p14 methylation occurred more frequently in former smokers than in current smokers (44% vs. 14%; P = 0.035). Taken together, our data suggest that analysis of promoter methylation in TSGs may provide a valuable biomarker for identification of groups with an elevated risk of cancer, such as smokers and ex-smokers.
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PMID:Aberrant p16 promoter methylation in smokers and former smokers with nonsmall cell lung cancer. 1291 69

The multistep process of tumorigenesis has not been decoded to date, although numerous investigations into probable molecular changes have meanwhile been conducted. However, not only DNA changes or loss of alleles cause deregulation of gene function, but also epigenetic alterations (e.g. methylation) result in functional loss. The INK4a-ARF (CDKN2A) locus, located on chromosome 9p21, encodes two functionally distinct tumor suppressor genes, p14ARF and p16INK4a, which play active roles in the p53 and Rb tumor suppressive pathways. We therefore examined not only p16 and p14 proteins, but also alterations of the INK4a-ARF locus, including methylation and loss of heterozygosity in benign and malignant tumors of the head and neck (squamous cell carcinomas and pleomorphic adenomas). In benign pleomorphic adenomas, methylation of p14ARF was found in 1 out of 42 (2%) cases, whereas alterations of p16INK4a occurred in 12/42 (29%) pleomorphic adenomas. In HNSCC, methylation of p16INK4a occurred in 16 out of 50 (32%) carcinomas. P14ARF was found to be methylated in 8 out of 50 cases (16%). Our results demonstrate that alterations of the INK4a-ARF locus are frequent and important events not only in the carcinogenesis of malignant, but also in benign tumors.
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PMID:Genetic and epigenetic alterations of 9p21 gene products in benign and malignant tumors of the head and neck. 1292 39

The UVB component of the solar spectrum induces DNA lesions that, in the absence of error-free DNA repair, may give rise during DNA replication to mutations in caretaker and gatekeeper genes. The DNA repair genes are the best candidates for caretaker genes as exemplified by the human hereditary xeroderma pigmentosum (XP) syndrome. Cultured XP cells are hypermutable after UVB irradiation. This increased mutation frequency is also found in gatekeeper genes, which govern signalling pathways implicated in the control of cellular proliferation, differentiation and survival of human epidermal keratinocytes. We describe and discuss the role of mutated gatekeeper genes in five specific signalling pathways which have been implicated in skin carcinogenesis. The pathways we focus on in this review are: (i) P16(INK4A)-CDK4/6-RB; (ii) P14(ARF)-HDM2-P53; (iii) Sonic hedgehog (SHH)/GLI; (iv) WNT/beta-catenin; and (v) Bone Morphogenetic Protein (BMP)/SMAD. 70-80% of XP skin cancers exhibit one or several mutations in the P53, PTCH-1, SMO or CDKN2A genes, the type and frequency of mutated genes being different between squamous cell (SCCs) and basal cell carcinomas (BCCs). In XP cancers, the typically UVB-induced CC to TT tandem transitions represent approximately 60% of total mutations compared to 10-15% in skin tumours from DNA repair-proficient patients. Acquired activation of the pathways described herein can alter proliferation and differentiation of keratinocytes, allowing a damaged cell to replicate and give rise to mutated daughter cells, then eventually to the development of the carcinogenic process following clonal selection.
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PMID:UVB-induced mutations in human key gatekeeper genes governing signalling pathways and consequences for skin tumourigenesis. 1452 Dec 17

The p16INK4A/CDKN2A (p16) tumor suppressor gene is known to be inactivated in up to 98% of human pancreatic cancer specimens. Chemically induced pancreatic tumors in Syrian golden hamsters have been demonstrated to share many morphological and biological similarities with human pancreatic tumors and represent a potentially suitable model for the evaluation of therapies targeting p16. The purpose of this study was to evaluate primary hamster pancreatic tumor specimens for potentially inactivating p16 alterations. Tumors were induced with N-nitroso-bis-(2-oxopropyl) amine, followed by two cycles of augmentation pressure, and were harvested on day 100. Foci of tumor cells were identified by light microscopy after staining with hematoxylin and eosin, and corresponding tumor tissues were excised for DNA extraction. The techniques of multiplex real-time PCR, direct sequencing and methylation-specific PCR were used to evaluate 30 tumor specimens for homozygous deletions, mutations and aberrant methylation of 5' CpG islands, respectively. Homozygous deletions were identified in 11 of 30 (36.7%) specimens, mutations were identified in four of 30 (13.3%) specimens, and aberrant methylation of 5' CpG islands was found in 14 of 30 (46.7%) specimens. The overall frequency of p16 alterations was 93.3% (28 of 30 specimens) and the majority of changes (83.3%) were noted to be secondary to methylation or homozygous deletion. The four mutations significantly impaired cyclin-dependent kinase 4 inhibitory activity, and two resulted in perturbation of the global structure of P16 protein. These findings indicate that p16 inactivation is a common event in chemically induced hamster tumors, and that this animal model is appropriate for comparative studies evaluating pancreatic cancer therapeutic strategies targeting p16.
Carcinogenesis 2004 Feb
PMID:Frequent p16INK4A/CDKN2A alterations in chemically induced Syrian golden hamster pancreatic tumors. 1460 95

Lung cancer from radon or (239)plutonium exposure has been linked to alpha-particles that damage DNA through large deletions and point mutations. We investigated the involvement of an epigenetic mechanism, gene inactivation by promoter hypermethylation in adenocarcinomas from plutonium-exposed workers at MAYAK, the first Russian nuclear enterprise established to manufacture weapons plutonium. Adenocarcinomas were collected retrospectively from 71 workers and 69 non-worker controls. Lung adenocarcinomas were examined from workers and non-worker controls for methylation of the CDKN2A (p16), O(6)-methylguanine-DNA methyltransferase (MGMT), death associated protein kinase (DAP-K), and Ras effector homolog 1 genes (RASSF1A). The prevalence for methylation of the MGMT or DAP-K genes did not differ between workers and controls, while a higher prevalence for methylation of the RASSF1A gene was seen in tumors from controls. In marked contrast, the prevalence for methylation of p16, a key regulator of the cell cycle, was increased significantly (P = 0.03) in tumors from workers compared with non-worker controls. Stratification of plutonium exposure into tertiles also revealed a striking dose response for methylation of the p16 gene (P = 0.008). Workers in the plutonium plant where exposure to internal radiation was highest had a 3.5 times (C.I. 1.5, 8.5; P = 0.001) greater risk for p16 methylation in their tumors than controls. This increased probability for methylation approximated the 4-fold increase in relative risk for adenocarcinoma in this group of workers exposed to plutonium. In addition, a trend (P = 0.08) was seen for an increase in the number of genes methylated (> or =2 genes) with plutonium dose. Here we demonstrate that exposure to plutonium may elevate the risk for adenocarcinoma through specifically targeting the p16 gene for inactivation by promoter methylation.
Carcinogenesis 2004 Jun
PMID:Plutonium targets the p16 gene for inactivation by promoter hypermethylation in human lung adenocarcinoma. 1474 12

Studies of the allelotype of human cancers have provided valuable insights into those chromosomes targeted for genetic inactivation during tumorigenesis. We present the comprehensive allelotype of 82 xenografted pancreatic or biliary cancers using 386 microsatellite markers and spanning the entire genome at an average coverage of 10 cM. Allelic losses were nonrandomly distributed across the genome and most prevalent for chromosome arms 9p, 17p, and 18q (>60%), sites of the known tumor suppressor genes CDKN2A, TP53, and MADH4. Moderate rates of loss (at any one locus) were noted for chromosome arms 3p, 6q, 8p, 17q, 18p, 21q, and 22q (40-60%). A mapping of individual loci of allelic loss revealed 11 "hot spots" of loss of heterozygosity (>30%) in addition to loci near known tumor suppressor genes, corresponding to 3p, 4q, 5q, 6q, 8p, 12q, 14q, 21q, 22q, and the X chromosome. The average genomic fractional allelic loss was 15.3% of all tested markers for the 82 xenografted cancers, with allelic loss affecting as little as 1.5% to as much as 32.1% of tested loci, a remarkable 20-fold range. We determined the chromosome location (in cM) of each of the 386 markers used based on mapping data available from the National Center for Biotechnology Information, and we provide the first distance-based estimates of chromosome material lost in a human epithelial cancer. Specifically, we found that the cumulative size of allelic losses ranged from 58 to 1160 cM, with an average loss of 561.32 cM/tumor. We compared the genomic fractional allelic loss of each xenografted cancer with known clinicopathological features for each patient and found a significant correlation with smoking status (P < 0.01). These findings offer new loci for investigation of the genetic alterations common to pancreaticobiliary cancers and aid the understanding of mechanisms of allelic loss in human carcinogenesis.
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PMID:Large-scale allelotype of pancreaticobiliary carcinoma provides quantitative estimates of genome-wide allelic loss. 1487 14


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