DNA methyltransferase3a expression is an independent poor prognostic indicator in gastric cancer
XueyuanLiping CaoHong-XiMa -Yanhong► ShangMei-ShanJinKongZhi-fangJia JiaDonghuiYin-PingWangJian JIANSuo SuoJingJiang
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AIM: To explore the alteration of DNA methyltransferase expression in gastric cancer and to assess its prognostic value.METHODS: From April 2000 to December 2010, 227men and 73 women with gastric cancer were enrolled in the study. The expression of DNA methyltransferases(DNMTs), including DNMT1, DNMT3a and DNMT3b,in the 300 cases of gastric carcinoma, of which 85 hadpaired adjacent normal gastric mucus samples, was evaluated by immunohistochemistry using a tissue microarray. Serum anti-Helicobacter pylori(H. pylori) IgG was detected by enzyme-linked immunosorbent assay(ELISA). The relationships between the above results and the clinicopathological characteristics were analyzed. Their prognostic value was evaluated using the Cox proportional hazards model.RESULTS: In gastric cancer, expression of DNMTs was mainly seen in the nucleus. Weak staining was also observed in the cytoplasm. Expression of DNMT1, DNMT3a and DNMT3b in gastric cancer was significantly higher compared to that in the paired control samples(60.0% vs 37.6%, 61.2% vs 4.7%, and 94.1% vs 71.8%, P < 0.01). The overall survival rate was significantly higher in the DNMT3a negative group than in the DNMT3a positive group in gastric cancer patients(Log-rank test, P = 0.032). No significant correlation was observed between DNMT1 and DNMT3b expression and the overall survival time(Log-rank test, P = 0.289, P = 0.347). Multivariate regression analysis indicated that DNMT3a expression(P = 0.025) and TNM stage(P < 0.001), but not DNMT1(P = 0.54) or DNMT3b(P = 0.62), were independent prognostic factors in gastric cancer. H. pylori infection did not induce protein expression of DNMTs.CONCLUSION: The results suggest that expression of DNMT3a is an independent poor prognostic indicator in gastric cancer. DNMT3a might play an important role in gastric carcinogenesis.Keywords:
DNMT3B
DNMT1
Tissue microarray
Log-rank test
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To explore the protein expressions of DNMT1, DNMT3a and DNMT3b in sera of lung cancer patients.Enzyme-linked immunosorbent assay (ELISA) method was used to measure the protein expressions of DNMT1, DNMT3a and DNMT3b in 136 lung cancer patients hospitalized at Department of Respiratory Diseases, First Affiliated Hospital, Zhengzhou University during September 2012 to June 2013. And 147 healthy controls were selected from a population of physical examination at Sixth People's Hospital of Zhengzhou. And the relationship was analyzed between protein expressions of DNMT1, DNMT3a and DNMT3b and clinic characteristics of lung cancer.The protein expressions of DNMT1, DNMT3a and DNMT3b in patients with lung cancer (15 ± 10, 997 ± 76 , 302 ± 25) were higher than those of the controls (13 ± 10, 344 ± 93, 108 ± 22). And there were statistical significance (t = 3.28, 62.51, 37.27; P = 0.021, 0.000, 0.000). The results of Logistic regression show that the protein expressions DNMT1, DNMT3a and DNMT3b increased morbidity for lung cancer (χ(2) = 14.811, 26.768, 12.057; P = 0.000, 0.000 0.001), especially so for DNMT1 (OR = 1.545, 95%CI: 1.238-1.928). No correlation existed between the protein expressions of DNMT1, DNMT3a, DNMT3b and histological types or stages (P > 0.05).The high protein expressions of serum DNMT1, DNMT3a and DNMT3b increase morbidity for lung cancer. And these markers may predict the early occurrence of lung cancer.
DNMT3B
DNMT1
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Objective To investigate the correlationship between DNMT3 a,DNMT3 b protein expressions and the stateof promoter methylation of ERα gene and ERα protein expression in the development of sporadic breast cancer.Methods A total of 180 patients with sporadic breast cancer and 30 patients with breast fibroadenoma were included in this study.Theexpressions of DNMT3 a and DNMT3 b protein were detected by immunohistochemical method.The state of promoter methyla-tion of ERα gene was detected by methylation specific PCR in 97 patients with sporadic breast cancer.Results There wereno significant differences in positive expression rates of DNMT3 a and DNMT3 b protein between breast fibroadenoma andbreast cancer.There were higher expression levels of DNMT3 a and DNMT3 b in breast cancer patient of Ⅲ~Ⅳ stages thanthose ofⅠ~Ⅱstages.The expression of DNMT3 a was significantly higher in patients with lymph node metastasis than that ofpatients without lymph node metastasis(P 0.05).Of 97 cases of breast cancer patients,ERα gene promoter methylation oc-curred in 39 cases(40.2%).The positive expression of DNMT3 a protein was positively correlated with the ERα gene methyla-tion(rS=0.250).The DNMT3 a protein expression showed a significant influence to the overall survival(OS) in patients ofbreast cancer(P=0.035),no significant influence to the disease-free survival(DFS)(P=0.064).DNMT3 b protein expressionshowed no significant influence to OS and DFS of patients with breast cancer(P = 0.914 and 0.961).Conclusion The posi-tive expressions of DNMT3 a and DNMT3 b are correlated with the invasion,metastasis and poor prognosis of sporadic breastcancer.DNMT3 a was positively correlated with the state of ERα gene promoter methylation.The inhibition of DNMT3 a andDNMT3b may have advantages in the prevention and treatment of sporadic breast cancer.
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To investigate the relationship between the expression of DNMT and clinical prognosis in adult patients with acute leukemia (AL), the mRNA expressions of DNMT, p15(INK4B), mdr1 were measured in 72 AL patients and 20 normal controls by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR); the ratio of p15 CpG land methylation was measured in 56 AL patients and 14 normal controls by methylation-specific PCR (MSP-PCR). The results showed that all three DNMT mRNA expressions in AL patients were significantly higher than that in normal controls (P < 0.01). When the internal control was changed into PCNA, a kind of cell proliferation marker gene, the difference still showed a statistic significance. All three DNMT genes were significantly expressed and positively correlated with AL patients, showing high synergistic expression, and there was a negative correlation between the levels of p15, mdr1 gene expression and DNMT. The complete remission (CR) rate in AL patients with the positive expression of all DNMT genes was significantly higher than that of AL patients with partially positive or negative expression (P < 0.01) of DNMT genes. In 56 AL patients, the P15I(NK4B) was completely methylated in 55.4% (31 of 56), partly methylated in 21.4% (12 of 56) and all 14 cases of normal controls were not methylated. It is concluded that DNMT genes are abnormally high expressed in adult AL patients, which lead to methylation-silence of tumor suppressor genes by CpG land hypermethylation, the AL patients with high expression of DNMT are more sensitive to chemotherapy, which may be a good prognostic factor for AL patients.
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We aimed to explore the association between aberrant DNA methylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) and human mutL homolog 1 (hMLH1) genes with gastric cancer.A total of 283 gastric cancer patients who were confirmed by pathological diagnosis were included in our study.Aberrant DNA methylation of MGMT and hMLH1 were detected.The proportions of DNA hypermethylation in MGMT and hMLH1 in cancer tissues were significantly higher than those in remote normal-appearing tissues.The DNA hypermethylation of MGMT was correlated with the tumor-necrosis-metastasis stage in gastric cancer tissues.Results showed that individuals with gastric cancer in the N1 and M1 stages had a significantly higher risk of DNA hypermethylation of MGMT in cancer tissues [odds ratio (OR) = 1.97, 95% confidence interval (CI) = 1.15-3.37 for the N1 stage; OR (95%CI) = 5.39 (2.08-14.98)for the M1 stage].In conclusion, we found that aberrant hypermethylation of MGMT could be a predictive biomarker for detecting gastric cancer.
O-6-methylguanine-DNA methyltransferase
DNA methyltransferase
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// Xiaoying Chen 1 , Yong Yang 1 , Jing Liu 1 , Bin Li 1 , Yan Xu 1 , Cong Li 2 , Qi Xu 2 , Guili Liu 1 , Yingmin Chen 1 , Jieer Ying 2 , Shiwei Duan 1 1 Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, China 2 Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China Correspondence to: Shiwei Duan, email: duanshiwei@nbu.edu.cn Jieer Ying, email: jieerying@aliyun.com Keywords: gastric cancer, N-Myc downstream regulated gene 4, DNA methylation, prognosis, diagnosis Received: September 27, 2016 Accepted: November 23, 2016 Published: December 22, 2016 ABSTRACT In order to assess whether N-Myc downstream regulated gene 4 ( NDRG4 ) methylation was associated with the diagnosis and prognosis of gastric cancer, we measured the methylation of NDRG4 promoter and gene body regions among 110 gastric cancer patients using quantitative methods (MethyLight and pyrosequencing). Both NDRG4 promoter and gene body methylation levels were increased in tumor tissues than paired adjacent normal tissues ( P < 0.001). NDRG4 gene body methylation was found to be significantly associated with age and tumor differentiation. NDRG4 promoter hypermethylation was proved to be a predictor of poor overall survival. However, opposite result was observed among The Cancer Genome Atlas (TCGA) cohort. The findings from gastric cell lines and public databases have suggested that NDRG4 methylation level was inversely associated with NDRG4 transcription level. Subsequent luciferase reporter gene assay showed that promoter CpG island but not gene body CpG island was able to upregulate gene expression. Collectively, NDRG4 promoter hypermethylation contributed to the risk of gastric cancer and predicted a poor prognosis in Chinese gastric cancer patients. Moreover, the combined methylation levels of NDRG4 promoter and gene body served as diagnostic biomarkers in gastric cancer.
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Objective To investigate the relationship between methylation of the 5′CpG island of the p16 tumor suppressor gene and carcinogenesis,depth of invasion and metastases of gastric cancer.Methods PCR based methylation assay was applied to examine a total of 46 samples of primary gastric cancer and 30 samples of control group for p16 gene methylation in Hpa Ⅱ,Msp Ⅰ,Sac Ⅱ sites.Results The methylation rate of the 5′CpG island of p16 gene was 0% in 30 samples of control group,and it was 28.3% in 46 samples of gastric cancer,there was significant difference beween two groups( P 0.05 ).The methylation rate of p16 gene was 47.8% and 8.7% in gastric cancer invading muscular layer and non invading group, respectively( P 0.05).The positive rate in poorly differentiated gastric cancer was 76.5% and significantely higher than in highly and moderately differentiated gastric cancer(0%)( P 0.05).The methyltion rate of p16 gene was detected in 44.4% of the gastric cancer with liver or lymph nodes metastases and in 24.3% of gastric cancer without metastases,there was no significant difference( P 0.05).The methylation rate was 25.0% in cardia and body of stomach cancer and 30.8% in angle of stomach and antrum( P 0.05).Conclusion The methylation of the 5′CpG island of the p16 tumor suppressor gene plays an importment role in gastric carcinogenesis.It is also suggested that the methylation of p16 gene is related to the depth of invasion and grade of differentiation of gastric cancer.There are no association between the methylation of p16 gene and growth ways,locations and metatastases of gastric cancer.
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Chemosensitivity assay
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AIM:To explore the alteration of DNA methyltransferase expression in gastric cancer and to assess its prognostic value. METHODS:From April 2000 to December 2010, 227 men and 73 women with gastric cancer were enrolled in the study.The expression of DNA methyltransferases (DNMTs), including DNMT1, DNMT3a and DNMT3b, in the 300 cases of gastric carcinoma, of which 85 had paired adjacent normal gastric mucus samples, was evaluated by immunohistochemistry using a tissue microarray.Serum anti-Helicobacter pylori (H.pylori ) IgG was detected by enzyme-linked immunosorbent assay (ELISA).The relationships between the above results and the clinicopathological characteristics were analyzed.Their prognostic value was evaluated using the Cox proportional hazards model. RESULTS:In gastric cancer, expression of DNMTs was mainly seen in the nucleus.Weak staining was also observed in the cytoplasm.Expression of DNMT1, DN-MT3a and DNMT3b in gastric cancer was significantly higher compared to that in the paired control samples (60.0%vs 37.6%, 61.2% vs 4.7%, and 94.1% vs 71.8%, P < 0.01).The overall survival rate was significantly higher in the DNMT3a negative group than in the DNMT3a positive group in gastric cancer patients (Log-rank test, P = 0.032).No significant correlation was observed between DNMT1 and DNMT3b expression and the overall survival time (Log-rank test, P = 0.289, P = 0.347).Multivariate regression analysis indicated that DNMT3a expression (P = 0.025) and TNM stage (P < 0.001), but not DNMT1 (P = 0.54) or DNMT3b (P = 0.62), were independent prognostic factors in gastric cancer.H. pylori infection did not induce protein expression of DNMTs. CONCLUSION:The results suggest that expression of DNMT3a is an independent poor prognostic indicator in gastric cancer.DNMT3a might play an important role in gastric carcinogenesis.
DNMT3B
DNMT1
Tissue microarray
Log-rank test
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Gastric cancer is the second leading cause of cancer death in the world. There is evidence that shows genetic and epigenetic change in stomach cancer is as a result of a variety of oncogenes, tumor suppressor genes, genes that repair the DNA, genes regulating cell cycle and cell adhesion molecules. P16 is an Inhibitor of protein kinase that is dependent on Cyclin D. Inactivation of this gene as a tumor suppressor gene, cause to cancer. This study was conducted to Investigation the P16 hyper-metylation status in serum of gastric cancer patients in Ardabil province as the prognostic factor for early diagnosis of gastric cancer. 82 Blood samples of patients with gastric cancer was prepared from Aras clinic of Imam Khomeini hospital. After DNA extraction from serum, using methylation-specific PCR assay it was examined the existence of hypermethylation in the P16 gene promoter. Incidence of free DNA in the serum of patients was 59.8%. P16 gene promoter was hyper methylated in 20.4% of subjects. Data analysis showed a statistically significant association between P16 methylation status and types of the adenocarcinoma. But there was no statistically significant association between methylation status of P16 with other features (age, sex, tumor location). This study showed P16 gene methylation of occur in some of gastric cancer patients. This result suggests that p16 methylation may be a prognostic marker for early diagnosis of gastric cancer.
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Alteration of aberrant DNA methylation is one of the most consistent epigenetic changes found in human cancers. DNA methylation is catalyzed by DNA methyltransferase (DNMT). In this study, we examined DNMT protein expression by immunohistochemistry in surgically resected hepatocellular carcinomas (HCCs). Sections of paraffin-embedded specimens were obtained from 95 patients with HCC between 1989 and 2002. The specimens were stained with anti-DNMTs (DNMT1, DNMT3a and DNMT3b) antibodies. There were statistically significant associations between DNMT protein expression and tumor differentiation (P < 0.05) and intrahepatic metastasis (P < 0.05). DNMT3a protein expression was significantly correlated with portal vein involvement of tumors (P < 0.05). The overall survival rates of patients with DNMT3a-positive HCCs and DNMT3b-positive HCCs were significantly lower than those of patients negative for these proteins (P < 0.005, respectively). To further evaluate the correlation between DNMT protein expression and patient survival, we classified patients into 3 groups: Group 1, DNMT1(+), 3a(–) and 3b(–); Group 2) DNMT1(+), 3a or 3b(+); and Group 3) DNMT1(+), 3a(+) and 3b(+). The overall survival rate of patients in Group 3 was significantly lower than those of patients in Groups 1 and 2 (P = 0.0009). In conclusion, the results of this study suggest that DNMT1, DNMT3a and DNMT3b are cooperatively involved in determining the extent of HCCs, and that DNMT protein overexpression in HCCs may be a predictive factor for poor survival.
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