Epigenetic Silencing of Cyclooxygenase-2 Affects Clinical Outcome in Gastric Cancer

2007 ◽  
Vol 25 (31) ◽  
pp. 4887-4894 ◽  
Author(s):  
Michiel F.G. de Maat ◽  
Cornelis J.H. van de Velde ◽  
Naoyuki Umetani ◽  
Pieter de Heer ◽  
Hein Putter ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Pilot Study ◽  
Patient Group ◽  
Methylation Status ◽  
Gene Promoter ◽  
Promoter Hypermethylation ◽  
Cyclooxygenase 2 ◽  
Time To Recurrence ◽  
Cox 2

PurposeOverexpression of cyclooxygenase-2 (COX-2) in gastric cancer has been shown to enhance tumor progression. We investigated whether silencing by promoter region hypermethylation of the COX-2 gene contributes to disease outcome in gastric cancer.Materials and MethodsCOX-2 methylation status was initially assessed by capillary array electrophoresis methylation–specific polymerase chain reaction (CAE-MSP) and COX-2 protein expression by immunohistochemistry (IHC) in 40 primary gastric cancer tissues in a pilot study. Prognostic end points of correlative studies of COX-2 methylation status were time to recurrence, overall survival, and standard clinicopathologic features. CAE-MSP analysis was then validated in a second independent gastric cancer population (n = 137).ResultsCOX-2 methylation was detected in 23% and 28% of the pilot and validation patient groups, respectively. COX-2 expression (IHC) in gastric tumors inversely correlated with COX-2 gene methylation status in the pilot study (P = .02). COX-2 methylation in tumors was significantly associated with lower T, N, and TNM stage in the validation patient group (P = .02, P = .006, and P = .008, respectively). Patients with COX-2 methylated tumors had significantly longer time to recurrence and improved overall survival in a multivariate analysis in the validation patient group (hazard ratio[HR], 0.49; 95% CI, 0.24% to 0.99%; HR, 0.62; 95% CI, 0.38% to 0.99%, respectively).ConclusionHypermethylation of COX-2 gene promoter was identified as an independent prognostic factor in gastric cancer patients. The results suggest promoter hypermethylation to be an important regulatory mechanism of COX-2 expression in gastric cancer and an important prognostic biomarker.

scholarly journals Analysis of smad4 gene promoter methylation in pancreatic and endometrial cancers

2017 ◽  
Vol 23 (2) ◽  
pp. 17-19
Author(s):  
Aleksandra Nikolic ◽  
Filip Opincal ◽  
Momcilo Ristanovic ◽  
Jovanka Trifunovic ◽  
Srbislav Knezevic ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Methylation Status ◽  
Gene Promoter ◽  
Promoter Hypermethylation ◽  
Surgical Removal ◽  
Smad4 Gene ◽  
Frequent Event ◽  
Cancer Types ◽  
Endometrial Cancers ◽  
Tumor Types

Background. Promoter hypermethylation of the SMAD4 gene has been registered in some cancer types, but in general doesn?t appear to be a frequent event in carcinogenesis. However, only a few published studies deal with this topic and not many cancer types have been analyzed. The aim of this study was to establish SMAD4 gene promoter methylation status in pancreatic and endometrial cancers. Methods. Patients included in the study (62 subjects) were diagnosed and surgically treated at the University of Belgrade, Clinical Center of Serbia. Patients with pancreatic carcinoma (17 subjects) underwent surgical removal of the pancreatic adenocarcinoma at the First Surgical Clinic, while the patients with endometrial carcinoma (45 subjects) underwent hysterectomy with adnexectomy at the Institute for Gynecology and Obstetrics. Extraction of DNA from fresh tissue samples was performed and the methylation status of the SMAD4 gene promoter was studied by a previously designed PCR-based HpaII and MspI restriction enzyme assay. The resulting PCR products were analyzed by electrophoresis in 2% agarose gels. Results. Neither of the analyzed samples was found to be hypermethylated. Conclusion. This is the first report on SMAD4 methylation status in pancreatic and endometrial tumor specimens, and supports the viewpoint that SMAD4 hypermethylation is not a common event in malignant tumors. Nevertheless, promoter hypermethylation remains a candidate mechanism for SMAD4 inactivation in malignant tissue as a potential cause of decreased or lost SMAD4 expression in certain tumor types, and should be further investigated in different tumor types and larger cohorts of patients.

CDH1 Gene Promoter Hypermethylation in Gastric Cancer

2006 ◽  
Vol 15 (1) ◽  
pp. 24-29 ◽  
Author(s):  
Monika Zazula ◽  
Ana Maria Ferreira ◽  
Jacek P. Czopek ◽  
Piotr Kolodziejczyk ◽  
Anna Sinczak-Kuta ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gene Promoter ◽  
Promoter Hypermethylation ◽  
Cdh1 Gene

Lower LINE-1 methylation is associated with promoter hypermethylation and distinct molecular features in gastric cancer

Epigenomics ◽  
2019 ◽  
Vol 11 (15) ◽  
pp. 1651-1659
Author(s):  
Sayumi Tahara ◽  
Tomomitsu Tahara ◽  
Noriyuki Horiguchi ◽  
Masaaki Okubo ◽  
Tsuyoshi Terada ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gastric Mucosa ◽  
Cpg Island ◽  
Methylation Status ◽  
Promoter Hypermethylation ◽  
Cpg Island Methylator Phenotype ◽  
Line1 Methylation ◽  
Methylator Phenotype ◽  
H Pylori ◽  
Mlh1 Methylation

Aim: To investigate the associations between LINE1 methylation, an indicator for genome-wide hypomethylation, molecular and clinicopathological characteristics of gastric cancer (GC) patients. Patients & methods: LINE1 methylation statuses were examined in paired cancerous, non-neoplastic mucosa from 217 GC and gastric mucosa from separate group of 224 noncancer patients. CpG island methylator phenotype, TP53 and KRAS mutation, MLH1 methylation status and promoter hypermethylation of GC related and H. pylori-related genes were examined. Results: Lower LINE1 methylation was observed in primary GC compared with non-neoplastic gastric mucosa and associated with CpG island methylator phenotype, TP53 mutation, MLH1 methylation and promoter hypermethylation of GC related and H. pylori-related genes. Conclusion: Lower LINE1 methylation correlates specific molecular subtypes and promoter hypermethylation in GC.

Prognostic Analysis of E-Cadherin Gene Promoter Hypermethylation in Patients with Surgically Resected, Node-Positive, Diffuse Gastric Cancer

2004 ◽  
Vol 10 (8) ◽  
pp. 2784-2789 ◽  
Author(s):  
Francesco Graziano ◽  
Federica Arduini ◽  
Annamaria Ruzzo ◽  
Italo Bearzi ◽  
Bostjan Humar ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gene Promoter ◽  
Promoter Hypermethylation ◽  
Diffuse Gastric Cancer ◽  
Node Positive ◽  
Prognostic Analysis ◽  
Resected Node ◽  
E Cadherin

Cyclooxygenase-2 Expression Is Related With Localization, Proliferation, and Overall Survival in Canine Melanocytic Neoplasms

2011 ◽  
Vol 48 (6) ◽  
pp. 1204-1211 ◽  
Author(s):  
C. M. Martínez ◽  
C. Peñafiel-Verdú ◽  
M. Vilafranca ◽  
G. Ramírez ◽  
M. Méndez-Gallego ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mitotic Index ◽  
Tumor Location ◽  
Cyclooxygenase 2 ◽  
Ki 67 ◽  
Melanocytic Tumors ◽  
Oral Neoplasms ◽  
Survival Frequency ◽  
Cox 2 ◽  
Proliferative Indices

A direct relationship has been firmly established between cyclooxygenase-2 (COX-2) expression and malignant behavior in human melanoma. This report examines the relationship between COX-2 expression and tumor location, mitotic and proliferative indices, degree of T CD3+ lymphocyte infiltration, overall survival, and frequency of recurrence and metastasis of 57 melanocytic tumors (25 oral and 32 cutaneous). COX-2 was highly or moderately expressed in 88% of oral neoplasms (22 of 25), whereas for their cutaneous counterparts, COX-2 expression was low or insignificant in 75% of cases (24 of 32). High and moderate COX-2 expression levels were observed in 73% of melanocytic tumors with a mitotic index ≥ 3 per 10 high-power fields (26 of 36), whereas in 81% of tumors with a mitotic index < 3 (17 of 21), expression was mild or absent. There were 41 cases with known clinical outcomes; of those showing high, moderate, and mild COX-2 expression, 83.3% (10 of 12), 37.5% (3 of 8), and 25% (2 of 8) died, respectively, whereas 100% of animals showing no COX-2 expression (13 of 13) were still alive at the last follow-up. COX-2 expression was statistically correlated with tumor location, mitotic and percentage Ki-67 proliferative indices, and overall survival, frequency of neoplastic recurrence and metastasis. Regression analysis also showed disease-specific predictive value for COX-2 expression for subjects with melanocytic neoplasms. Additionally, only high COX-2 expression showed significant differences in overall survival, in comparison with moderate, mild, or absent expression. These results suggest that high COX-2 expression may be considered a prognostic biomarker and potentially as a target for therapeutic and preventive strategies in canine melanocytic neoplasms.

scholarly journals Stromal, rather than epithelial cyclooxygenase-2 (COX-2) expression is associated with overall survival of breast cancer patients

BMC Cancer ◽  
2014 ◽  
Vol 14 (1) ◽  
Author(s):  
Justyna Urban ◽  
Łukasz Kuźbicki ◽  
Grzegorz Szatkowski ◽  
Agata Stanek-Widera ◽  
Dariusz Lange ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Cancer Patients ◽  
Cyclooxygenase 2 ◽  
Breast Cancer Patients ◽  
Cox 2

scholarly journals Influence of Cyclooxygenase-2 (COX-2) Gene Promoter Polymorphism at Position −765 on Skin Cancer after Renal Transplantation

2010 ◽  
Vol 130 (8) ◽  
pp. 2134-2136 ◽  
Author(s):  
François Aubin ◽  
Cécile Courivaud ◽  
Jamal Bamoulid ◽  
Alexandre Loupy ◽  
Marina Deschamps ◽  
...  
Keyword(s):  
Renal Transplantation ◽  
Skin Cancer ◽  
Gene Promoter ◽  
Promoter Polymorphism ◽  
Cyclooxygenase 2 ◽  
Cox 2 ◽  
Gene Promoter Polymorphism

Predicting gene promoter methylation in lung tumors through examination of sputum and serum

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7208-7208
Author(s):  
S. A. Belinsky ◽  
M. Grimes ◽  
D. Johnson ◽  
D. Levy ◽  
J. Schiller
Keyword(s):  
Lung Cancer ◽  
Cell Function ◽  
Biological Fluids ◽  
Methylation Status ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Gene Promoter ◽  
Promoter Hypermethylation ◽  
Phase Iii ◽  
Advanced Lung Cancer

7208 Background: Personalized medicine may be a key approach in improving survival for advanced lung cancer. Success for this approach is seen with the response of cancer patients with an activating mutation within the epidermal growth factor receptor to the growth fact inhibitor, gefitinib. Genes involved in all types of normal cell function are targeted for inactivation by promoter hypermethylation during lung cancer development. This makes gene-specific promoter hypermethylation an attractive target for novel treatment strategies. One obstacle to targeted therapy is accessibility of tissue from peripheral tumors for methylation analysis. The purpose of this study was to determine the predictive power of sputum and serum to detect NSCLC through analysis for methylation of genes in these fluids. Methods: Tissue, serum, and sputum were obtained from 72 stage III NSCLC patients participating in a Phase III trial of Carboplatin, Paclitaxel and Radiotherapy, With or Without Thalidomide (ECOG 3598). Methylation specific PCR assessed methylation of the p16, MGMT, DAPK, RASSF1A, PAX5-α, PAX5-β, H-cadherin, and GATA5 genes. Results: At least one gene was methylated in 89% of tumors. Prevalence for methylation ranged from 15–47% and did not differ between gender. Methylation of ≥ 3 genes was seen in ∼50% of tumors. The agreement between sputum or serum in classifying methylation status of any gene in the tumor ranged from 54– 69%. The reduced sensitivity was presumably due in part to absence of tumor DNA in the biological fluids of methylation positive tumors. Logistic regression models revealed 3.1 (CI, 1.2, 8.2) and 4.2 (1.1, 16.1) increased odds for methylation of the p16 and MGMT gene, respectively in tumors if the serum or sputum was positive for methylation. The effect of tumor histology for predicting methylation using sputum and serum is being examined. Conclusion: These studies demonstrate for genes such as p16 and MGMT the possibility of interrogating biological fluids to predict for methylation in the primary tumor. (Supported by CA-89551). No significant financial relationships to disclose.

A Pilot Study of Irinotecan Combined with 5-Fluorouracil and Leucovorin for the Treatment of Chinese Patients with Locally Advanced and Metastatic Gastric Cancer

2009 ◽  
Vol 95 (4) ◽  
pp. 432-437 ◽  
Author(s):  
Qiu Li ◽  
Jing Chen ◽  
Xin Zhao ◽  
Xude Yin ◽  
Kai Mei ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Pilot Study ◽  
Partial Response ◽  
Locally Advanced ◽  
Metastatic Gastric Cancer ◽  
Chinese Patients ◽  
Grade 3 ◽  
Anti Tumor Activity ◽  
Comparative Trials

Aims and background The FOLFIRI regimen was evaluated for its anti-tumor activity and toxicity in Chinese patients with locally advanced and metastatic gastric cancer. Methods and study design Treatment consisted of irinotecan, 180 mg/m2 (90-min infusion), leucovorin, 200 mg/m2 (2-h infusion), followed by 5-fluorouracil, 400 mg/m2 (bolus), and then 5-fluorouracil, 600 mg/m2 (22-h continuous infusion) on days 1 and 2, every 14 days. Results Twenty-six patients, of whom 17 were pretreated, were included in the study. Partial response was observed in 9 patients (37.5%). The overall disease control rate was 83.3%. Median progression-free and overall survival was 6.8 and 11.2 months, respectively. Grade 3–4 neutropenia was observed in 6 patients (23.1%) and grade 2–3 diarrhea in 5 (19.2%). No treatment-related deaths occurred. Conclusions The results demonstrate that the FOLFIRI regimen is an active regimen with acceptable toxicity for Chinese patients with advanced and metastatic gastric cancer that merits further investigation in comparative trials.

scholarly journals p16INK4Aand p14ARFGene Promoter Hypermethylation as Prognostic Biomarker in Oral and Oropharyngeal Squamous Cell Carcinoma: A Review

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
A. Al-Kaabi ◽  
L. W. van Bockel ◽  
A. J. Pothen ◽  
S. M. Willems
Keyword(s):  
Squamous Cell Carcinoma ◽  
Clinical Outcome ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Methylation Status ◽  
Gene Promoter ◽  
Promoter Hypermethylation ◽  
Oropharyngeal Squamous Cell Carcinoma ◽  
Molecular Profile ◽  
Tumor Type

Head and neck squamous cell carcinoma is a heterogeneous group of tumors with each subtype having a distinct histopathological and molecular profile. Most tumors share, to some extent, the same multistep carcinogenic pathways, which include a wide variety of genetic and epigenetic changes. Epigenetic alterations represent all changes in gene expression patterns that do not alter the actual DNA sequence. Recently, it has become clear that silencing of cancer related genes is not exclusively a result of genetic changes such as mutations or deletions, but it can also be regulated on epigenetic level, mostly by means of gene promoter hypermethylation. Results from recent studies have demonstrated that DNA methylation patterns contain tumor-type-specific signatures, which could serve as biomarkers for clinical outcome in the near future. The topic of this review discusses gene promoter hypermethylation in oral and oropharyngeal squamous cell carcinoma (OSCC). The main objective is to analyse the available data on gene promoter hypermethylation of the cell cycle regulatory proteinsp16INK4Aandp14ARFand to investigate their clinical significance as novel biomarkers in OSCC. Hypermethylation of both genes seems to possess predictive properties for several clinicopathological outcomes. We conclude that the methylation status ofp16INK4Ais definitely a promising candidate biomarker for predicting clinical outcome of OSCC, especially for recurrence-free survival.

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