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)

Hepatocellular carcinoma (HCC) most commonly arises from chronic inflammation due to viral infection, as a result of genetic and epigenetic abnormalities. A global picture of epigenetic changes in HCC is lacking. We used methylated CpG island amplification microarrays (MCAMs) to study 6458 CpG islands in HCC and adjacent preneoplastic tissues [chronic hepatitis (CH) or liver cirrhosis (LC)] in comparison with normal liver tissues where neither viral infection nor hepatitis has existed. MCAM identified 719 (11%) prominent genes of hypermethylation in HCCs. HCCs arising from LC had significantly more methylation than those arising from CH (1249 genes or 19% versus 444 genes or 7%, P < 0.05). There were four patterns of aberrant methylation: Type I (4%, e.g. matrix metalloproteinase 14) shows a substantially high methylation level in adjacent tissue and does not increase further in cancer. Type II (55%, e.g. RASSF1A) shows progressively increasing methylation from adjacent tissue to HCC. Type III (4%, e.g. GNA14) shows decreased methylation in adjacent tissue but either similar or increased methylation in HCC. Type IV (37%, e.g. CDKN2A) shows low levels of methylation in normal tissue and adjacent tissue but high levels in HCC. These DNA methylation changes were confirmed by quantitative pyrosequencing methylation analysis in representative 24 genes and were analyzed for correlation with clinicopathological parameters in 38 patients. Intriguingly, methylation in the Type IV genes is characteristic of moderately/poorly differentiated cancer. Our global epigenome analysis reveals distinct patterns of methylation that are probably to represent different pathophysiologic processes in HCCs.
Carcinogenesis 2008 Oct
PMID:Variable DNA methylation patterns associated with progression of disease in hepatocellular carcinomas. 1863 56

Barrett esophagus (BE) is an established precursor of esophageal adenocarcinoma (AdenoCa). One hundred and one cases of BE diagnosed by esophageal biopsy and resections were examined morphologically for dysplasia. These were categorized as BE without dysplasia (n=25), indefinite for dysplasia (IND, n=17), low-grade dysplasia (LGD, n=18), high-grade dysplasia (HGD, n=15), and AdenoCa (n=26). Immunostaining for p16 (INK4A/CDKN2A), Cyclin D1 (CCND1), Ki-67, and alpha-methylacyl-CoA racemase (AMACR) was employed to assess their potential as diagnostic discriminators. Abnormal p16 expression (negative, cytoplasmic, or combined cytoplasmic and nuclear staining) was present in all categories, rising from 68% in BE without dysplasia to 100% in AdenoCa, with cytoplasmic staining only showing a significant correlation with the severity of dysplasia. Cyclin D1 expression was present in almost all cases, but high expression (>50% cells positive) was displayed mostly in HGD and AdenoCa (46.7% and 42.3%, respectively). Ki-67 index increased with the severity of dysplasia and labeling extended from the lower third of the crypts to the superficial epithelium. The frequency of AMACR-positivity was 12% in BE, 47.1% in IND, 44.4% in LGD, 93.3% in HGD, and 96.2% in AdenoCa. The intensity and extent of AMACR staining also increased with the severity of dysplasia. Aberrant p16 and high-cyclin D1 expression may reflect early genetic events during the progression of Barrett-associated carcinogenesis. Cytoplasmic staining of p16 is specific. It may represent a different pathway of p16 dysfunction. The pattern and extent of Ki-67 staining and AMACR overexpression are useful additional parameters for identifying dysplasia in BE.
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PMID:p16, cyclin D1, Ki-67, and AMACR as markers for dysplasia in Barrett esophagus. 1866 38

p16(CDKN2A) is one of the most important tumor-suppressor genes and has been investigated widely in recent years for its role in oral carcinogenesis, but few have explored the relationship between its RNA and protein, especially in precancerous tissues. The aim of this study was to explore the relationship of mRNA and protein level of p16(CDKN2A) in rat tongue carcinogenesis process induced by 4-nitroquinoline-1-oxide. By the use of semi-quantitative RT-PCR, immunohistochemistry (IHC) and Western Blot, histologically normal, premalignant and invasive squamous cell carcinoma samples from the animal model were explored respectively. The results showed the levels of mRNA of p16(CDKN2A) did not significantly change during the carcinogenesis process when compared with controls. However, detectable level of P16 protein expression was lost in both the dysplasia and carcinoma groups. We could conclude that p16(CDKN2A) in 4NQO-induced rat tongue carcinogenesis might be inactivated predominantly by posttranscriptional regulation.
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PMID:p16(CDKN2A) expression during rat tongue carcinogenesis induced by 4-nitroquinoline-1-oxide. 1880 14

High-risk types of HPV express the oncoproteins, E6 and E7, that can inactivate TP53 and RB1, respectively, and thus take control of both cell cycle and apoptosis. Herein, the mRNA expression profiles of 24 G1/S checkpoint genes were analysed in cancer and squamous intraepithelial lesions (SIL) of the uterine cervix. In total 35 squamous cervical carcinomas, 26 high-grade SIL (HSIL), 33 low-grade SIL (LSIL) tissues, and 28 normal uterine cervix specimens as controls were assessed by RT-PCR. Five genes were found to be upregulated only in tumours, RBL2, E2F2, CDK6, CCNE1 and MYC; eight in tumours and HSILs, E2F1, E2F3, E2F5, CCND1, CDK2, CDKN1B, PCNA and POLA, and five in tumours, HSILs and LSILs, TP53, E2F4, CDKN1A, CDKN2A and DHFR. MDM2 was found to be upregulated in SIL, while RBL1 was found to be downregulated in all three groups of cases. TP73 exhibited lower levels in carcinomas; however, its exon 13-containing isoforms were increased and exon 2-containing isoforms were reduced in both cancer and HSIL. Three genes, RB1, CDK4 and CDKN2D, did not exhibit any significant alteration in gene expression. Hierarchical clustering revealed that this set of G1/S checkpoint genes was able to discriminate the total 122 samples into groups of disease and non-disease with only 8 exceptions (6.6%). Our data suggest that deregulation of G1/S phase transition in cervical carcinogenesis is a progressive process. Certain clusters of genes are activated very early in pre-cancerous SILs while others are activated later, during malignant transformation. The ability of this array of markers to identify disease status suggests that it could be used for diagnostic purposes.
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PMID:Deregulation of the G1/S phase transition in cancer and squamous intraepithelial lesions of the uterine cervix: a case control study. 1881 14

The observation that the age-specific incidence curve of many carcinomas is approximately linear on a double logarithmic plot has led to much speculation regarding the number and nature of the critical events involved in carcinogenesis. By a consideration of colorectal and pancreatic cancers in the Surveillance Epidemiology and End Results (SEER) registry we show that the log-log model provides a poor description of the data, and that a much better description is provided by a multistage model that predicts two basic phases in the age-specific incidence curves, a first exponential phase until the age of approximately 60 followed by a linear phase after that age. These two phases in the incidence curve reflect two phases in the process of carcinogenesis. Paradoxically, the early-exponential phase reflects events between the formation (initiation) of premalignant clones in a tissue and the clinical detection of a malignant tumor, whereas the linear phase reflects events leading to initiated cells that give rise to premalignant lesions because of abrogated growth/differentiation control. This model is consistent with Knudson's idea that renewal tissue, such as the colon, is converted into growing tissue before malignant transformation. The linear phase of the age-specific incidence curve represents this conversion, which is the result of recessive inactivation of a gatekeeper gene, such as the APC gene in the colon and the CDKN2A gene in the pancreas.
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PMID:Age-specific incidence of cancer: Phases, transitions, and biological implications. 1893 80

The global increase in lung cancer burden, together with its poor survival and resistance to classical chemotherapy, underscores the need for identification of critical molecular events involved in lung carcinogenesis. Here, we have applied quantitative profiling of DNA methylation states in a panel of five cancer-associated genes (CDH1, CDKN2A, GSTP1, MTHFR, and RASSF1A) to a large case-control study of lung cancer. Our analyses revealed a high frequency of aberrant hypermethylation of MTHFR, RASSF1A, and CDKN2A in lung tumors as compared with control blood samples, whereas no significant increase in methylation levels of GSTP1 and CDH1 was observed, consistent with the notion that aberrant DNA methylation occurs in a tumor-specific and gene-specific manner. Importantly, we found that tobacco smoking, sex, and alcohol intake had a strong influence on the methylation levels of distinct genes (RASSF1A and MTHFR), whereas folate intake, age, and histologic subtype had no significant influence on methylation states. We observed a strong association between MTHFR hypermethylation in lung cancer and tobacco smoking, whereas methylation levels of CDH1, CDKN2A, GSTP1, and RASSF1A were not associated with smoking, indicating that tobacco smoke targets specific genes for hypermethylation. We also found that methylation levels in RASSF1A, but not the other genes under study, were influenced by sex, with males showing higher levels of methylation. Together, this study identifies aberrant DNA methylation patterns in lung cancer and thus exemplifies the mechanism by which environmental factors may interact with key genes involved in tumor suppression and contribute to lung cancer.
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PMID:Quantitative analysis of DNA methylation profiles in lung cancer identifies aberrant DNA methylation of specific genes and its association with gender and cancer risk factors. 1911 9

Some cases of pancreatic cancer (PC) are described to cluster within families. With the exception of PALLD gene mutations, which explain only a very modest fraction of familial cases, the genetic basis of familial PC is still obscure. Here the literature was reviewed in order to list the known genes, environmental factors, and health conditions associated with PC or involved in the carcinogenesis of the pancreas. Most of the genes listed are responsible for various well-defined cancer syndromes, such as CDKN2A (familial atypical mole-multiple melanoma, FAMMM), the mismatch repair genes (Lynch Syndrome), TP53 (Li-Fraumeni syndrome), APC (familial adenomatous polyposis), and BRCA2 (breast-ovarian familial cancer), where PC is part of the cancer spectrum of the disease. In addition, in this review I ranked known/possible risk factors extending the analysis to the hereditary pancreatitis (HP), diabetes, or to specific environmental exposures such as smoking. It appears that these factors contribute strongly to only a small proportion of PC cases. Recent work has revealed new genes somatically mutated in PC, including alterations within the pathways of Wnt/Notch and DNA mismatch repair. These new insights will help to reveal new candidate genes for the susceptibility to this disease and to better ascertain the actual contribution of the familial forms.
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PMID:Genetic predisposition and environmental risk factors to pancreatic cancer: A review of the literature. 1915 Apr 14

The presence of frequent methylation of CpG islands (CGIs), designated as the CpG island methylator phenotype in some cancers, is associated with distinct clinicopathological characteristics, including gene amplification, in individual tumor types. Amplification of HER2 in human breast cancers is an important prognostic and therapeutic target, but an association between HER2 amplification and frequent CGI methylation is unknown. To clarify the association, we here quantified methylation levels of promoter CGIs of 11 genes, which are unlikely to confer growth advantage to cells, in 63 human breast cancers. The number of methylated genes in a cancer did not obey a bimodal distribution, and the 63 cancers were classified into those with frequent methylation (n = 16), moderate methylation (n = 26) and no methylation (n = 21). The incidence of HER2 amplification was significantly higher in the cancers with frequent methylation (11 of 16) than in those with no methylation (2 of 21, P = 0.001). Also, the number of methylated genes correlated with the degree of HER2 amplification (r = 0.411, P = 0.002). Correlation analysis with clinicopathological characteristics and methylation of CDKN2A, BRCA1 and CDH1 revealed that frequent methylation had significant correlation with higher nuclear grades (P = 0.001). These showed that frequent methylation had a strong association with HER2 amplification in breast cancers and suggested that frequent methylation can be a determinant of various characteristics in a fraction of human breast cancers.
Carcinogenesis 2009 Mar
PMID:Association between frequent CpG island methylation and HER2 amplification in human breast cancers. 1916 84

3-methylcholanthrene (MCA) and diethylnitrosamine (DEN) are typical genotoxic carcinogens that can induce tumors in a variety of human and rodent tissues. However, the epigenetic mechanisms underlying their tumorigenesis are unclear. In this study we used a MCA/DEN-induced multistep lung carcinogenesis rat model to study the evolution of alterations in DNA methylation. Rats were treated with a single dose of MCA and DEN in iodized oil by left intra-bronchial instillation. The animals were killed on days 15, 35, 55, 65 and 75 and samples of various pathological phases during carcinogenesis were obtained on these days. The status of global methylation was analyzed for each sample using a monoclonal antibody specific for 5-methycytosine (5-mC) and quantified by image analysis software. We found that the degree of global methylation was, in general, higher in basal cells compared to luminal cells of normal, precancerous and tumor tissues. The combined 5-mC scores of different types of tissues decreased gradually during the progression of carcinogenesis. We also used methylation-sensitive arbitrarily primed PCR (MS-AP-PCR) to screen a total of eight differentially methylated DNA fragments in both precancerous and tumor tissues isolated using laser capture microdissection (LCM), and observed that both unique hypomethylation and hypermethylation fragments coexist after exposure to genotoxic carcinogens. Remarkably, epigenetic alterations in p16 (CDKN2A), but not in p15 (CDKN2B), were observed, and these correlated with the presence of pathologic lung lesions and loss of p16 protein expression. Moreover, defective expression of p16 in methylated primary tumor cell lines recovered markedly after treated with 5-aza-2'-deoxycytidine (5-aza-dC). These results suggest that DNA methylation alterations are an early event in tumorigenesis and play an important role during MCA/DEN-induced multistep rat lung carcinogenesis.
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PMID:Dynamic changes in DNA methylation during multistep rat lung carcinogenesis induced by 3-methylcholanthrene and diethylnitrosamine. 1940 58

DNA methylation contributes to carcinogenesis by silencing key tumor suppressor genes. Here we report an ultrasensitive and reliable nanotechnology assay, MS-qFRET, for detection and quantification of DNA methylation. Bisulfite-modified DNA is subjected to PCR amplification with primers that would differentiate between methylated and unmethylated DNA. Quantum dots are then used to capture PCR amplicons and determine the methylation status via fluorescence resonance energy transfer (FRET). Key features of MS-qFRET include its low intrinsic background noise, high resolution, and high sensitivity. This approach detects as little as 15 pg of methylated DNA in the presence of a 10,000-fold excess of unmethylated alleles, enables reduced use of PCR (as low as eight cycles), and allows for multiplexed analyses. The high sensitivity of MS-qFRET enables one-step detection of methylation at PYCARD, CDKN2B, and CDKN2A genes in patient sputum samples that contain low concentrations of methylated DNA, which normally would require a nested PCR approach. The direct application of MS-qFRET on clinical samples offers great promise for its translational use in early cancer diagnosis, prognostic assessment of tumor behavior, as well as monitoring response to therapeutic agents.
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PMID:MS-qFRET: a quantum dot-based method for analysis of DNA methylation. 1944 57


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