Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Epigenetic mechanisms involving DNA methylation and chromatin remodeling are important in silencing tumor suppressor genes (TSG) in various malignancies, including renal cell carcinoma (RCC). DLC1 (deleted in liver cancer 1)/ARHGAP7 is a recently identified 8p22 candidate TSG. Frequent methylation of the DLC1 promoter with resultant gene silencing has been reported in several tumors, but not in RCC yet. We examined DLC1 promoter methylation in 34 primary RCCs and the corresponding non-malignant tissues, and the correlation of DLC1 methylation with the clinicopathological characteristics of RCC patients. Although DLC1 methylation and downregulation were only detected in one of seven RCC cell lines using methylation-specific PCR (MSP) and semi-quantitative reverse-transcription PCR, we found that the DLC1 promoter was methylated in 35% (12/34) of primary RCC tumors, which was further confirmed by direct sequencing of MSP products and high-resolution bisulfite genomic sequencing. In contrast, only one of the 34 (3%) non-malignant renal tissues had weak methylation. Aberrant DLC1 methylation appeared to be a relatively early event during renal tumorigenesis since 33% of the RCC tumors with pT1 (TNM staging) showed methylation, which is similar to other late stage tumors. Thus, our results demonstrated that DLC1 methylation occurs in a subset of RCC tumors and may play a role in renal carcinogenesis.
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PMID:Aberrant methylation of the 8p22 tumor suppressor gene DLC1 in renal cell carcinoma. 1702 74

Esophageal squamous cell carcinoma (SCC) remains the leading cause of cancer related deaths in Linzhou (formerly Linxian), the highest incidence area for esophageal cancer (EC) in Henan, northern China. In China, gastric cardia adenocarcinoma (GCA) shares very similar geographic distribution with SCC, suggesting the possibility of similar risk factors involved in SCC and GCA carcinogenesis in these areas. However, the underlying genetic alterations for esophageal and gastric cardia carcinogenesis, especially for the molecular difference between SCC and GCA, are largely unknown. The present study was thus undertaken to determine the difference in chromosomal aberrations in SCC (n = 37) and GCA (n = 31) using the comparative genomic hybridization method (CGH). All the patients were from Linzhou, Henan, a high-risk geographic region for both SCC and GCA. CGH results showed that chromosomal aberrations with different degrees were identified both in SCC and GCA. In SCC, chromosomal profile of DNA copy number was characterized by most frequently detected gains at 8q (29/37, 78%), 3q (24/37, 65%) and 5p (19/37, 51%); and frequently detected losses at 3p (21/37, 57%), 8p and 9q (14/37, 38%). In GCA, the frequently detected gains were identified at 20q (13/31, 42%), 6q (12/31, 39%) and 8q (11/31, 35%); the DNA copy number losses in GCA occurred frequently at 17p (17/31, 55%), 19p (15/31, 48%) and 1p (14/31, 45%). Statistically, there were evident differences between SCC and GCA in DNA copy number gains at 8q, 3q, 5p and 20q (P < 0.05) and in losses at 3p, 8p, 5q, 17p and 18q (P < 0.05). Gains at 8q were frequently observed in both SCC and GCA. Gains at 3q and 8p were frequently observed in TNM stage III of both SCC and GCA. The present CGH results provide candidate regions that may contain specific related genes involved in SCC and GCA in the Linzhou population. Gains at 8q, 3q and 5p and losses at 3p, 8p and 9q were specifically implicated in SCC; gains at 20q, 6q and 8q and losses at 17p, 19p and 1p were specifically implicated in GCA; gains at 8q were implicated in both SCC and GCA.
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PMID:Comparative genomic hybridization: comparison between esophageal squamous cell carcinoma and gastric cardia adenocarcinoma from a high-incidence area for both cancers in Henan, northern China. 1706 89

Lung cancer remains the leading cause of cancer death worldwide. Overall 5-year survival is approximately 10-15% and despite curative intent surgery, treatment failure is primarily due to recurrent disease. Conventional prognostic markers are unable to determine which patients with completely resected disease within each stage group are likely to relapse. To identify a gene signature associated with recurrent squamous cell carcinoma (SCC) of lung, we analyzed primary tumor gene expression for a total of 51 SCCs (Stages I-III) on 22 323 element microarrays, comparing expression profiles for individuals who remained disease-free for a minimum of 36 months with those from individuals whose disease recurred within 18 months of complete resection. Cox proportional hazards modeling with leave-one-out cross-validation identified a 71-gene signature capable of predicting the likelihood of tumor recurrence and a 79-gene signature predictive for cancer-related death. These two signatures were pooled to generate a 111-gene signature which achieved an overall predictive accuracy for disease recurrence of 72% (77% sensitivity, 67% specificity) in an independent set of 58 (Stages I-III SCCs). This signature also predicted differences in survival [log-rank P=0.0008; hazard ratio (HR), 3.8; 95% confidence interval (CI), 1.6-8.7], and was superior to conventional prognostic markers such as TNM stage or N stage in predicting patient outcome. Genome-wide profiling has revealed a distinct gene-expression profile for recurrent lung SCC which may be clinically useful as a prognostic tool.
Carcinogenesis 2007 Mar
PMID:Expression profiling defines a recurrence signature in lung squamous cell carcinoma. 1708 75

Cells expressing high-risk human papillomavirus (HPV) E7 protein display impaired checkpoint control after DNA damage and exhibit elevated rates of mutagenesis. Repression of HPV E7 expression results in the subsequent accumulation of hypophosphorylated retinoblastoma protein and repression of the Cdc25A genes. No study has been conducted to elucidate the role of Cdc25A in the development and progression of human oral carcinomas. To confirm Cdc25A protein expression together with HPV, immunohistochemistry, Western blotting, polymerase chain reaction (PCR), and reverse transcriptase (RT)-PCR were performed using various histological subtypes of oral carcinomas. Cdc25A protein was localized predominantly in the cell nuclei in carcinomas, and high expression was found in 54% of primary tumors. HPV-16 E7 was not found in non-neoplastic oral tissues, whereas it was observed in eight (36%) of 22 oral carcinomas. We found a significant correlation between Cdc25A over-expression and HPV-16 E7 positive carcinomas. There was a strong positive correlation between Cdc25A over-expression and tumor size and TNM stage. This study suggests that Cdc25A is likely to be an important mediator in the progression of oral tumors, and HPV-16 E7 may be a sensitive indicator of the involvement of viral oncogenes in oral carcinogenesis.
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PMID:High-risk human papillomavirus type 16 E7 oncogene associates with Cdc25A over-expression in oral squamous cell carcinoma. 1711 Nov 24

Adenocarcinoma of the oesophagus and gastro-oesophageal junction are rapidly increasing in incidence and have a well described sequence of carcinogenesis: the Barrett's metaplasia-dysplasia-adenocarcinoma sequence. During recent years there have been changes in the knowledge surrounding disease progression, cancer management and histopathology specimen reporting. Tumours around the gastro-oesophageal junction (GOJ) pose several specific challenges. Numerous difficulties arise when the existing TNM staging systems for gastric and oesophageal cancers are applied to GOJ tumours. The issues facing the current TNM staging and GOJ tumour classification systems are reviewed in this article. Recent evidence regarding the importance of several histopathologically derived prognostic factors, such as circumferential resection margin status and lymph node metastases, have implications for specimen reporting. With the rising use of multimodal treatments for oesophageal cancer it is important that the response of the tumour to this therapy is carefully documented pathologically. In addition, several controversial and novel areas such as endoscopic mucosal resection, lymph node micrometastases and the sentinel node concept are being studied. We aim to review these aspects, with special relevance to oesophageal and gastro-oesophageal cancer specimen reporting, to update the surgical oncologist with an interest in upper gastrointestinal cancer.
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PMID:Emerging aspects of oesophageal and gastro-oesophageal junction cancer histopathology - an update for the surgical oncologist. 1711 94

Hypoxia-inducible factor-1 (HIF-1)alpha expression was studied in the gastric carcinogenesis sequence and as a prognostic factor in surgically resected gastric and gastro-oesophageal junction tumours. Protein expression was examined using immunohistochemistry on formalin-fixed biopsies of normal mucosa (n=20), Helicobacter pylori associated gastritis (n=24), intestinal metaplasia (n=24), dysplasia (n=12) and intestinal (n=19) and diffuse (n=21) adenocarcinoma. The relationship between HIF-1alpha expression and prognosis was assessed in resection specimens from 177 patients with gastric and gastro-oesophageal junction adenocarcinoma. Hypoxia-inducible factor-1alpha expression was not observed in normal gastric mucosa but increased in density (P<0.01) and intensity (P<0.01) with progression from H. pylori-associated gastritis, intestinal metaplasia, dysplasia to adenocarcinoma. The pattern of staining in the resection specimens was focally positive in 49 (28%) and at the invasive tumour edge in 41 (23%). Invasive edge expression was associated with lymph node metastases (P=0.034), advanced TNM stage (P=0.001) and was an adverse prognostic factor for cancer-specific survival (P=0.019). In univariate analysis and in comparison with tumours not expressing HIF-1alpha, invasive edge staining was associated with a hazard ratio of 1.6 (95% CI 1.0-2.5) and focally positive staining a hazard ratio of 0.7 (95% CI 0.5-1.2). Hypoxia-inducible factor-1alpha lost prognostic significance in multivariate analysis. The results suggest HIF-1alpha is involved in gastric carcinogenesis and disease progression, but is only a weak prognostic factor for survival.
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PMID:Hypoxia-inducible factor-1alpha expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastro-oesophageal adenocarcinomas. 1717 85

The aim of the present study was to evaluate the tissue expression of squamous cell carcinoma antigen (SCCA) in oesophageal dysplasia and squamous cell carcinoma (SCC) with reference to its clinico-pathologic and prognostic significance. Immunohistochemistry using SCCA polyclonal antibody was performed on SCCs from 61 surgical oesophagectomies. Fifteen cases of low-grade dysplasia (LGD) and 37 non-coexistent high-grade dysplasia (HGD) were also sampled from these materials, together with sixteen chronic cases of oesophagitis. SCCA immunoreactivity was present in the maturative compartments of all normal epithelia and oesophagitis. LGDs showed no SCCA immunoreactivity in the dysplastic proliferative component but only in the superficial normal layers. In 94.6% of HGDs, no SCCA immunoreactivity was detected throughout the thickness of the epithelium. In SCCs, SCCA expression higher than 25% was found in 54% of cases. SCCA positivity showed an inverse correlation with histological grade, whereas no statistically significant correlation was found with TNM classifications, stage, or survival. SCCA is not expressed in early oesophageal carcinogenesis but, in SCC, it represents an indicator of histologic differentiation. In differentiated SCC, SCCA may represent a negative factor for cancer invasiveness, through inhibition of proteases.
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PMID:Expression pattern of squamous cell carcinoma antigen in oesophageal dysplasia and squamous cell carcinoma. 1752 76

COX-2 expression in tumour cells has been associated with carcinogenesis in many human neoplasms, including head and neck cancer, while the COX-1 isoform of the cyclooxygenase enzyme is constitutively expressed in normal tissues. We measured COX-1 and COX-2 m-RNA expression in samples of both oral cancer and matched oral mucosa from 22 patients by RealTime RT-PCR; clinic pathological data (grading, TNM staging, inflammation, follow-up) of all patients were available for statistical evaluation. Most of the tumor samples in our study expressed at least one cyclooxygenase enzyme (COX-1 or COX-2 mRNA) more than their matched normal oral mucosa (p<0.05), with no correlation with the entity of inflammation, and a significant inverse relationship was found between COX-1 and COX-2 in each sample. Higher levels of COX-2 expression were associated with poor disease-free survival (p<0.05), but not with overall survival and higher tumor stage and grade. Our results suggest that COX-1 may play a role in oral carcinogenesis, and could be regarded as a potential therapeutic target by chemo preventive drugs; moreover, COX-2 expression might be addressed as a new prognostic tool in the clinical management of OSCC.
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PMID:Cyclooxygenase isozymes in oral squamous cell carcinoma:a real-time RT-PCR study with clinic pathological correlations. 1762 43

The effect of preoperative radio chemotherapy on lymphatic drainage and intraoperative gamma probe-guided sentinel lymph node detection has yet not been investigated. In this study, we study 13 patients with SCC. Sentinel lymph node (SLN) imaging of the patients was performed using SPECT-CT. Special care was taken to use identical injection sites for both studies. Imaging comprised planar and SPECT, iterative reconstruction and were viewed with the co-registered CT image. The results were validated by comparison with the histological results of intraoperative gamma probe detection and histology of the completed neck dissection. Identical SLNs were found in 6/13 patients. In 2/13 cases SLN biopsies were false-negative. In 4/13 patients preoperative SLN imaging identified more/additional nodes than the initial imaging, whereas fewer nodes were seen in 3/13 patients. Neither the primary tumor site nor the TNM stage was predictive for changes in the lymphatic drainage pattern. No constant effect of irradiation could be demonstrated. Preoperative radio chemotherapy has an unpredictable influence on the lymphatic drainage pattern in HNSCC. Consequently, the intraoperative gamma probe-guided sentinel lymph node detection after radio chemotherapy does not reveal the SLN of carcinogenesis. Thus, we advise fused functional/anatomical imaging (SPECT-CT) before and after radiochemotherapy if the SLN concept is utilized in HNSCC.
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PMID:Validity of sentinel lymph node (SLN) detection following adjuvant radiochemotherapy (RCT) in head and neck squamous cell carcinoma (HNSCC). 1799 97

Gastric cancer is the second most frequent cause of cancer death worldwide, yet the precise mechanisms underlying the different subtypes of gastric carcinogenesis are poorly understood. Improvements in the diagnosis and prognosis of gastric cancer over classical clinicopathologic findings such as TNM stage, age or macroscopic tumor type, now include novel techniques for superficial endoscopic examination, and new strategies for genetically analyzing biopsied specimens. The development of gastric adenocarcinomas, such as that of many tumor classes, represents the cumulative effects of several different types of mutations, and it is now recognized that both the loss of normal DNA repair, as well as the mutation, loss or inhibition of tumor suppressor genes contribute to the genetic instability leading to cancer. It might be logically anticipated that the combined burden of these two defects would synergize in carcinogenesis, but the extent to which such pathways cooperate in promoting cancer is still not yet well understood. Clearly, an enhanced appreciation of the mechanisms and interactions of these pathways would aid development of diagnosis and treatment options.
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PMID:Interaction of microsatellite instability and loss of heterozygosity in adenocarcinoma: multiple markers in adenocarcinoma: an introduction to 'Genetic changes in Slovenian patients with gastric adenocarcinoma evaluated in terms of microsatellite DNA'. 1799 33


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