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)

Dysregulation of cell cycle control may lead to genomic instability, neoplastic transformation and tumor progression. In terms of the particular roles in regulation of the cell-cycle, p21(WAF1) causes growth arrest through inhibition of cyclin-dependant kinases required for G1/S transition. P16 (INK4A) and p15 (INK4B) are thought to act as tumor suppressors, since their inactivation and/or deletion are observable in various types of malignancies. Cyclin D1 is hypothesized to control cell cycle progression through the G1-S check point. The present study evaluated p21 expression, p16 and p15 gene deletion and cylin D1 expression in bladder carcinoma among Egyptian patients, in relation to different clinicopathological features of the tumors and presence or absence of bilharziasis. Tissue specimens were obtained from 132 patients with bladder carcinoma and 50 normal tissue samples from the same patients served as control. P21 was determined by Western blot (WB) and enzyme immunoassay (EIA), p16 and p15 gene deletions were examined by polymerase chain reaction (PCR) and Cyclin D1 was detected by WB. Levels of p21 were lower in malignant tumors than in normal tissues. Lower expression of p21 was evident in lymph node positive, well differentiated tumors and squamous cell carcinoma (SCC) than in lymph node negative, poorly differentiated tumors and transitional cell carcinoma (TCC). In all normal samples, p15 and p16 genes were detected while cyclin D1 was not detected. P16 and p15 genes were deleted in 38.7% (41/106) and 30.2% (32/106) of bladder tumors respectively. The deletion of both genes was associated with poor differentiation grade and presence of bilharziasis. P16 deletion was also correlated to advancing tumor stage. Cyclin D1 was expressed in 57.5% of bladder tumors (69/120), where its expression was correlated to early stage, well differentiation grade, schistomiasis, and low levels of p21. Cell cycle is dysregulated in bladder carcinoma. This was evident from the increased expression of cyclin D1, the decreased levels of p21 and the deletion of p15 and p16 genes. Moreover, p16 and p15 gene deletion was related to tumor progression and might have a role in bilharzial bladder carcinogenesis. Cyclin D1 over-expression appears to be an early event in bladder cancer and might explain bilharzial associated bladder carcinogenesis.
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PMID:Cell cycle regulators in bladder cancer: relationship to schistosomiasis. 1559 May 62

Cancer found in the post-operative remnant stomach includes both newly developed cancer after surgery for benign-disease (PRC) and metachronous multiple cancer (MRC). Differences in the carcinogenic pathway between PRC and MRC have been suspected from clinical studies. However, no study has demonstrated the difference in molecular alteration between these diseases. P16 is inactivated predominantly by epigenetic change, rather than genetic alteration. We analyzed the methylation status and protein expression of the p16 gene in cancers of the remnant stomach. Eleven lesions of PRC, 24 lesions of MRC and corresponding non-cancerous tissue, as well as 13 primary gastric cancer (PC) lesions were examined. DNA was extracted by the micro-dissection method from paraffin-embedded surgical specimens. The methylation status of the promoter CpG island of the p16 gene was examined by using a methylation-specific polymerase chain reaction technique. To detect protein expression, immunohistochemical staining was employed. p16 promoter hypermethylation was observed more often in remnant gastric cancer than in PC. A significantly more frequent hypermethylation in the p16 gene was found in PRC (64%) than in MRC (21%) or PC (23%). Moreover, a significant correlation was found between p16 promoter hypermethylation and diminishment of protein expression in cancers of the remnant stomach. Silencing of the p16 gene by methylation of its promoter CpG island was suggested as a unique molecular mechanism in the carcinogenesis of PRC compared with MRC or PC.
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PMID:Frequent p16 CpG island hypermethylation in primary remnant gastric cancer suggesting an independent carcinogenic pathway. 1646 21

Studies have revealed that Epstein-Barr virus (EBV) infection, genetic aberration, and environmental factors are of importance in the development of nasopharyngeal carcinoma (NPC), although the definite mechanism remains to be fully elucidated. The aim of our study is to investigate using tissue microarray analysis whether differential expression of EBV-encoded small RNA-1 (EBER-1) and several tumor-related genes were associated with NPC carcinogenesis. Immunohistochemistry and in situ hybridization were performed on tissue microarrays containing 148 NPCs and 164 noncancerous nasopharyngeal epithelia (NPE) with different morphologic features. We found that overexpressions of EBER-1 hybridization signals, p53, p21ras, and bcl-2 proteins and loss expressions of p16 and p27 proteins were significantly increased in NPC tissues compared with normal NPE and hyperplastic NPE (P </= .001). The overexpressions of EBER-1 and p53 (P < .001) and the loss expressions of P16 (P < .001) and P27 (P = .005) were also significantly higher and more frequently observed in NPC than in dysplastic NPE. The positive expression of EBER-1 hybridization signals in NPC had significant associations with overexpressions of p53 (P < .001), p21ras (P = .041), and bcl-2 proteins (P < .001) and loss expression of p16 protein (P = .001). Further analysis confirmed that the abnormal expression of p53, p16, and p27 proteins occurred in the earliest stage of nasopharyngeal epithelial carcinogenesis. In the final logistic regression analysis model, the positive hybridization signals of EBER-1 and the abnormal expression of p53, p16, and p27 proteins were independent contributions for nasopharyngeal carcinogenesis, and EBER-1 was the most significant, independent predictor of nasopharyngeal carcinogenesis (hazard ratio = 13.412, 95% confidence interval 6.179-29.111, P < .001). In conclusion, EBV infection, together with overexpressions of p53, and loss expressions of p16 and p27 proteins are involved in the multistep process of human nasopharyngeal epithelial carcinogenesis.
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PMID:Differential expression of Epstein-Barr virus-encoded RNA and several tumor-related genes in various types of nasopharyngeal epithelial lesions and nasopharyngeal carcinoma using tissue microarray analysis. 1664 58

Epigenetic mechanisms in carcinogenesis may have a significant role in the development of colorectal cancer. To investigate this phenomenon in early-stage disease, promoter methylation status in the tumour suppressor genes APC, MGMT, hMLH1, P14/P14ARF, and CDKN2A/P16 was investigated in 78 colorectal adenomas. These had previously been characterized for mutations of APC, KRAS, and TP53 genes and for chromosomal abnormality by comparative genomic hybridization (CGH). APC hypermethylation was seen in 52 tumours (66.7%). APC showed either methylation or mutation in 66 lesions (84.6%), but these events were not statistically associated. MGMT methylation was detected in 39 cases (50%). Adenomas with this abnormality showed a significantly lower number of chromosomal changes by CGH (p < 0.02), confirming that DNA repair defect of this type is associated with a lower level of chromosomal instability. An hMLH1 methylation defect was seen in only one adenoma (1.3%), from a patient who had a synchronous cancer showing the same defect. Methylation of P14 (P14ARF) was seen in 31 adenomas (39.7%) and CDKN2A (P16) abnormality in 25 (32.1%). DNA methylation at two or more loci was seen in 46 tumours (59%), while 11 lesions (14.1%) showed no evidence of hypermethylation at any of the loci studied. Methylation at any or all of MGMT, P14 or P16 was significantly associated with APC methylation (p = 0.01). Those neoplasms with more than two methylated genes showed significantly fewer chromosomal abnormalities than adenomas with one or no methylated loci (p < 0.001). There was no association between specific individual chromosomal abnormalities, APC, KRAS or TP53 mutations and any pattern of methylation abnormality. We conclude that methylation abnormality is very common in pre-invasive colorectal neoplasia, and that high level methylation is associated with low level chromosomal instability.
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PMID:Relationship between point gene mutation, chromosomal abnormality, and tumour suppressor gene methylation status in colorectal adenomas. 1690 13

Promoter hypermethylation is responsible for gene inactivation during carcinogenesis. It has been proposed that there is some degree of specificity in the set of genes that become altered by this mechanism in distinct tumor types. To understand whether promoter hypermethylation may differentiate the site of origin, 49 lung adenocarcinomas from 31 lung primaries and 18 metastases from colorectal primaries, respectively, were tested for the presence of this alteration in the APC, CDH1, DAPK, GSTP1, MLH1, MGMT, P14, P16, RARbeta2, RASSF1, sFRP1 and WIF-1 genes. A distinct profile was apparent for the 2 groups of lung tumors and the frequencies of promoter hypermethylation at sFRP1 and WIF-1, 2 genes involved in Wnt signaling, and at CDH1 were significantly higher in colorectal metastases than in lung primaries, whereas methylation of the APC promoter was significantly more common in lung primary adenocarcinomas. Some tumors showed concomitant APC, sFRP1 and WIF-1 gene inactivation, indicating that multiple DNA methylation events must have occurred to definitively down-regulate the signaling through Wnt. However, promoter hypermethylation at the APC and CDH1 genes tended to be mutually exclusive (Fisher's exact test, p = 0.006), suggesting a similar role in carcinogenesis. In conclusion, we propose that inactivation by promoter hypermethylation at the APC, CDH1, sFRP1 and WIF-1 genes may contribute to the discrimination of lung primary adenocarcinomas from colorectal metastasis to the lung, and report the simultaneous presence of methylation at the promoters of multiple genes involved in the Wnt signaling. This may have biological consequences for carcinogenesis.
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PMID:Wnt signaling promoter hypermethylation distinguishes lung primary adenocarcinomas from colorectal metastasis to the lung. 1699 Nov 25

The association between human papillomavirus (HPV) infection and carcinogenesis has long been established in literature, with the strongest evidence for its role in cervical carcinoma. The role of HPV in urological tumors has been investigated and sporadic reports have linked HPV infection to bladder, prostate, renal, penile, and testicular cancer. Although less rigorously studied, there are a few conflicting results about the role of HPV in the development of malignant renal tumors. Moreover, no data are available for association of HPV DNA and expression of P16 in benign renal tumors. Formalin-fixed, paraffin-embedded tissues from 62 renal tumors (40 clear cell, 9 papillary, and 3 chromophobe renal cell carcinomas, 1 collecting duct carcinoma, 2 urothelial carcinoma of renal pelvis and 7 oncocytomas) were immunostained with low-risk and high-risk HPV DNA (6, 11, 16, 18, 31, 33, 42, 51, 52, 56, 58). Tissue microarray sections of 62 tumors were stained with P16 by immunohistochemistry. Signal amplified colorimetric in situ hybridization was performed on microarray sections using biotinylated probes for HPV subtypes 6, 11, 16, 18. A nuclear dot-like signal was considered positive for low-risk and high-risk HPV by immunohistochemistry and in situ hybridization and nuclear or cytoplasmic staining is considered positive for P16. No staining for HPV DNA and P16 was found in any type of renal tumors. Our results support that HPV does not seem to play a role in the development of benign and malignant renal tumors.
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PMID:Human Papillomavirus DNA and P16INK4A are not detected in renal tumors with immunohistochemistry and signal-amplified in situ hybridization in paraffin-embedded tissue. 1712 41

Aberrant DNA methylation of CpG site in the gene promoter region has been confirmed to be closely associated with carcinogenesis. In this present study, a new method based on the allele-specific extension on microarray technique for detecting changes of DNA methylation in cancer was developed. The target gene regions were amplified from the bisulfite treated genomic DNA (gDNA) with modified primers and treated with exonuclease to generate single-strand targets. Allele-specific extension of the immobilized primers took place along a stretch of target sequence with the presence of DNA polymerase and Cy5-labeled dGTP. To control the false positive signals, the hybridization condition, DNA polymerase, extension time and primers design were optimized. Two breast tumor-related genes (P16 and E-cadherin) were analyzed with this present method successfully and all the results were compatible with that of traditional methylation-specific PCR. The experiments results demonstrated that this DNA microarray-based method could be applied as a high throughput tool for methylation status analysis of the cancer-related genes, which could be widely used in cancer diagnosis or the detection of recurrence.
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PMID:Allele-specific extension on microarray for DNA methylation analysis. 1796 40

The understanding of the biology of pancreatic carcinoma has greatly benefited from studies of genetic alterations and molecular expression in experimental models as well as in pre-cancerous and cancerous tissues by mean of molecular amplification and large scale transcriptome analysis. P16, TP53, DPC4/Smad4 tumor suppressor pathways are genetically inactivated in the majority of pancreatic carcinomas, whereas oncogenic k-ras is activated. The activating mutation of the K-ras oncogene on codon 12 seems to occur early in pancreatic carcinogenesis and detecting its mutation in tumor samples could have a clinical relevance in term of positive (improvement of current histological diagnosis) and differential diagnosis (versus chronic pancreatitis) of pancreatic cancer. At a late stage of tumor development, an increase of telomerase activity, an over expression of growth factors and/or their receptors (EGF, nerve growth factor, gastrin, bombesin), of proangiogenic factors (VEGF, FGF, PDGF), of invasiveness factors (metalloproteinases, E-cadherin, beta integrin, urokinase and tissue plasminogen activator) occur. All these molecular events contribute to the progression and to the metastatic potential of this carcinoma. New markers and targets are currently studied among microRNA and epigenetics events such as methylation and acetylation. Among all these molecular markers, some are now tested for their potential clinical interest in term of diagnosis or therapeutic target.
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PMID:[New molecular targets in pancreatic cancer]. 1854 14

Primary adenosquamous cell carcinomas (Ad-SCCs) of the colon and rectum are rare malignancies with a poor prognosis, in comparison to adenocarcinoma alone. Different roles of human papilloma virus (HPV) in its pathogenesis have been reported and the role of P16 in Ad-SCCs has not been explored. This report presents five cases of Ad-SCC of the colon to explore the clinicopathological features and the roles of P16, HPV 6/11, and 16/18. There was no confirmed evidence to support the relationship between the infection of HPV 6/11, 16/18, and pathogenesis of Ad-SCC of the colon. P16 overexpression was not related to HPV carcinogenesis and there might be another mechanism of P16 upregulation in Ad-SCC of the colon.
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PMID:Primary adenosquamous carcinoma of the colon: report of five cases. 1956 53

Molecular insights into the human papillomavirus (HPV)-induced cervical carcinogenesis led to the discovery of biomarkers for cervical disease. The detection of cellular proteins that are overexpressed by HPV-infected cells, such as tumor suppressor protein p16(INK4a), might play an important role in future cervical cancer screening strategies. P16(INK4a) immunostaining correlates with the severity of cytological and histological abnormalities, but shows some methodological shortcomings such as the lack of standardized methodology and interobserver variability. This study evaluated quantitative reverse transcriptase PCR (RT-PCR) as an alternative tool to analyze p16(INK4a) overexpression as a biomarker for transforming HPV-infections in a liquid-based cervical cytology (LBC) setting. Sixty LBC samples, divided in three groups based on their cytological diagnosis, were subjected to HPV typing and analysis of p16 expression by immunocytochemistry and RT-PCR. The analytical sensitivity of the RT-PCR was determined by spiking HeLa and HaCaT cells. P16(INK4a) expression measured by RT-PCR did not correlate with the cytological diagnosis or HPV status (HPV-positivity, infection type and HPV16-positivity). The spiking experiment proved that, to detect increased biomarker expression by RT-PCR, about 1.0% dysplastic cells is required within a pool of normal keratinocytes. In conclusion, RT-PCR analysis of biomarker expression is not appropriate for cervical screening purposes. In typical LBC samples, the biomarker transcripts of the dysplastic cells are diluted by the RNA of the normal cells in such a manner that their overexpression cannot be detected by RT-PCR.
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PMID:Biomarkers in cervical screening: quantitative reverse transcriptase PCR analysis of P16INK4a expression. 1991 Jul 96


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