Realgar (α-As4S4) Treats Myelodysplastic Syndromes through Reducing DNA Hypermethylation / 中国结合医学杂志

DNA hypermethylation is an epigenetic modification that plays a critical role in the oncogenesis of myelodysplastic syndromes (MDS). Aberrant DNA methylation represses the transcription of promotors of tumor suppressor genes, inducing gene silencing. Realgar (α-As4S4) is a traditional medicine used for the treatment of various diseases in the ancient time. Realgar was reported to have efficacy for acute promyelocytic leukemia (APL). It has been demonstrated that realgar could efficiently reduce DNA hypermethylation of MDS. This review discusses the mechanisms of realgar on inhibiting DNA hypermethylation of MDS, as well as the species and metabolisms of arsenic in vivo.

Promoter-associated DNA methylation & expression profiling of genes (FLT 3, EPB41L3 & SFN) in patients with oral squamous cell carcinoma in the Khasi & Jaintia population of Meghalaya, India

Background & objectives: Oral squamous cell carcinoma is one of the most lethal forms of cancer, and its aetiology has been attributed to both genetic and epigenetic factors working in liaison to contribute to the disease. Epigenetic changes especially DNA methylation is involved in the activation or repression of gene functions. The aim of this study was to investigate the DNA methylation pattern and expression profiling of the promoter regions of FMS-related tyrosine kinase 3 (FLT3), erythrocyte membrane protein band 4.1-like 3 (EPB41L3) and stratifin (SFN) genes in oral cancer within the Khasi and Jaintia tribal population of Meghalaya in North East India. Methods: Quantitative methylation analyses of the selected genes were carried out by MassARRAY platform System, and the relative expression profiling was carried out by real-time polymerase chain reaction. Results: Quantitative methylation results indicated that the level of methylation was significantly higher (hypermethylated) for FLT3 and EPB41L3 and significantly lower (hypomethylated) for SFN in tumour tissues as compared to the adjacent paired normal tissue. Expression profiling was in concurrence with the methylation data whereby hypermethylated genes showed low mRNA level and vice versa for the hypomethylated gene. Interpretation & conclusions: The findings show that hyper- and hypomethylation of the selected genes play a potential role in oral carcinogenesis in the selected Khasi and Jaintia tribal population of Meghalaya. The methylation status of these genes has not been reported in oral cancer, so these genes may serve as promising biomarkers for oral cancer diagnosis as well as in disease monitoring.

Reversal of Hypermethylation in Tumor Suppressor Genes Using Phytochemicals in Cervical Cancer

Cervical cancer is most familiar neoplasm among women worldwide. Surgery, radiotherapy, and chemotherapy are common treatments, however high stage tumors have frequently poor prognosis. HPV 16 and 18 are major etiological factors for cervical cancer. Likewise, epigenetics is the study of inherited changes and modulated gene expression without alteration in DNA sequences. In mammals epigenetic modifications include DNA methylation, histone modifications and miRNA. Phytochemicals are mainly contained in fruits, seeds, and vegetables as well as in foods supplements. Numerous dietary compounds exhibit potent anti-tumor activities through the reversion of epigenetic alterations associated to oncogenes activation and inactivation of tumor suppressor genes in cervical cancer cell lines SiHa and HeLa, demethylation of the tumour suppressor genes such as RARβ2, MGMT, RASSF1A, DAPK etc. Reversal of hypermethylated genes as a tumor-suppressor gene, is related to inhibition of cell proliferation, development and differentiation. The impact of phytochemicals lead to the reversal of hypermethylation which may help to cure cervical cancer. This study concludes the effect of phytochemicals on genetic and epigenetic modifications and reveals how these modifications help to prevent various types of cancers and improve health outcomes.

CBS promoter hypermethylation increases the risk of hypertension and stroke

OBJECTIVES: Cystathionine β-synthase is a major enzyme in the metabolism of plasma homocysteine. Hyperhomocysteinemia is positively associated with hypertension and stroke. The present study was performed to examine the possible effects of Cystathionine β-synthase promoter methylation on the development of hypertension and stroke. METHODS: Using quantitative methylation-specific PCR, we determined the Cystathionine β-synthase methylation levels in 218 healthy individuals and 132 and 243 age- and gender-matched stroke and hypertensive patients, respectively. The relative changes in Cystathionine β-synthase promoter methylation were analyzed using the 2-ΔΔCt method. The percent of the methylated reference of Cystathionine β-synthase was used to represent the Cystathionine β-synthase promoter methylation levels. RESULTS: In this study, the Cystathionine β-synthase promoter methylation levels of hypertensive and stroke participants were both higher than that of the healthy individuals (median percentages of the methylated reference were 50.61%, 38.05% and 30.53%, respectively, all p<0.001). Multivariable analysis showed that Cystathionine β-synthase promoter hypermethylation increased the risk of hypertension [odds ratio, OR (95% confidence interval, CI)=1.035 (1.025-1.045)] and stroke [OR (95% CI)=1.015 (1.003-1.028)]. The area under the curve of Cystathionine β-synthase promoter methylation was 0.844 (95% CI: 0.796-0.892) in male patients with hypertension and 0.722 (95% CI: 0.653-0.799) in male patients with stroke. CONCLUSION: Cystathionine β-synthase promoter hypermethylation increases the risk of hypertension and stroke, especially in male patients.

Expression and significance of hypermethylation in cancer 1 protein and ovarian cancer gene 1 protein in ovarian cancer tissue / 重庆医学

Objective To study the expression of hypermethylated gene 1 protein and ovarian cancer gene 1 protein in ovarian cancer and its relationship with the pathological features of ovarian cancer,and to explore its significance in ovarian cancer.Methods Sixty-three cases of ovarian cancer specimens and 63 cases of normal ovarian tissue were taken from January 2014 to December 2015 at the First Hospital of Jilin University.Western blot was used to detect the expression of hypermethylated gene 1 protein and ovarian cancer gene 1 protein in ovarian cancer tissues and normal ovarian tissues,and to analyze the relationship between the expression of two proteins and ovarian cancer.Results The expression of hypermethylated gene 1 protein and ovarian cancer gene 1 protein in ovarian cancer tissues were significantly lower than that in normal ovarian tissues (P＜0.05).There was no significant difference in the expression of hypermethylated gene 1 protein in different staging,different degree of differentiation and different pathological types in ovarian cancer (P＞0.05).The expression of ovarian cancer gene 1 protein in ovarian cancer stage Ⅰ was higher than that in stage Ⅱ and Ⅲ-Ⅳ (P＜0.05).The expression of ovarian cancer gene 1 protein in ovarian cancer stage Ⅱ was higher than that in stage Ⅲ-Ⅳ (P＜0.05).The expression of ovarian cancer gene 1 protein in high differentiation of ovarian cancer was significantly higher than that in moderately differentiated and poorly differentiated (P＜0.05).There was no significant difference between ovarian cancer gene 1 protein expression and poorly differentiated ovarian cancer (P＞0.05).There was no sig nificant difference in the expression of ovarian cancer gene 1 protein in different pathological types of ovarian cancer (P＞0.05).Conclusion Hypermethylatel gene,protein participate in the occurrence of ovarian cancer,the ovarian cancer gene 1 protein is only related to ovarian cancer clinical stage and degree of differentiation.

p15(Ink4b) Loss of Expression by Promoter Hypermethylation Adds to Leukemogenesis and Confers a Poor Prognosis in Acute Promyelocytic Leukemia Patients / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The p15(Ink4b) gene exerts its influence as an inhibitor of cyclin-dependent kinases and is frequently associated with hematological malignancies. Inactivation of this gene through DNA methylation has been found to be the most prevalent epigenetic alteration reported, with a high frequency in all French-American-British subtypes of acute myeloid leukemias, including acute promyelocytic leukemia (APL). In this study,we investigated the prognostic significance of p15 gene promoter hypermethylation and its expression in APL patients of Kashmir (North India). MATERIALS AND METHODS: p15 gene promoter hypermethylation was conducted by methylation-specific polymerase chain reaction, while its subsequent expression analysis was carried out by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Of the 37 patients, 16 (43.2%) were found to have methylated p15 genes. Of these 16 cases, seven (43.8%) were methylated partially and nine (56.2%) were found to have complete methylation. Moreover, nine of the 37 patients (24.3%) who presented with leukocytosis at their baseline had complete p15 gene methylation as well (p < 0.05). Semiquantitative RT-PCR showed a complete loss of p15 expression in nine patients with complete methylation coupled with leukocytosis (p=0.031), while seven patients with partial methylation showed decreased p15 expression. Six patients relapsed during the maintenance phase of treatment and were found to have a completely methylated p15 gene and no p15 mRNA. CONCLUSION: Complete methylation and loss of p15 gene expression causes susceptibility to relapse and decreased survival in APL patients. Thus, p15 promoter hypermethylation is a prospective prognostic indicator and a reliable clinical aid in assessment of patients with APL.

p15(Ink4b) Loss of Expression by Promoter Hypermethylation Adds to Leukemogenesis and Confers a Poor Prognosis in Acute Promyelocytic Leukemia Patients / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The p15(Ink4b) gene exerts its influence as an inhibitor of cyclin-dependent kinases and is frequently associated with hematological malignancies. Inactivation of this gene through DNA methylation has been found to be the most prevalent epigenetic alteration reported, with a high frequency in all French-American-British subtypes of acute myeloid leukemias, including acute promyelocytic leukemia (APL). In this study,we investigated the prognostic significance of p15 gene promoter hypermethylation and its expression in APL patients of Kashmir (North India). MATERIALS AND METHODS: p15 gene promoter hypermethylation was conducted by methylation-specific polymerase chain reaction, while its subsequent expression analysis was carried out by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Of the 37 patients, 16 (43.2%) were found to have methylated p15 genes. Of these 16 cases, seven (43.8%) were methylated partially and nine (56.2%) were found to have complete methylation. Moreover, nine of the 37 patients (24.3%) who presented with leukocytosis at their baseline had complete p15 gene methylation as well (p < 0.05). Semiquantitative RT-PCR showed a complete loss of p15 expression in nine patients with complete methylation coupled with leukocytosis (p=0.031), while seven patients with partial methylation showed decreased p15 expression. Six patients relapsed during the maintenance phase of treatment and were found to have a completely methylated p15 gene and no p15 mRNA. CONCLUSION: Complete methylation and loss of p15 gene expression causes susceptibility to relapse and decreased survival in APL patients. Thus, p15 promoter hypermethylation is a prospective prognostic indicator and a reliable clinical aid in assessment of patients with APL.

Significance of detecting miR-145 hypermethylation in non-small cell lung cancer / 实用医学杂志

Objective To explore the significance of detecting miR-145 hypermethylation in non-small cell lung cancer (NSCLC). Methods Seventy-five NSCLC tissues and adjacent tissues was collected from May 2012 to January 2015. The methylation status of miR-145 promoter was tested by bisulfite sequencing PCR (BSP) and the expression of miR-145 evaluated by ISH. The correlation between miR-145 methylation and clinical parameters , and the relationship between miR-145 methylation and expression were statistically analyzed. Results The hypermethy-lation ratio of miR-145 in NSCLC tissues was higher than that in the adjacent tissues. Hypermethylation of miR-145 was correlated with NSCLC differentiation stage, but not with gender and age. In NSCLC, miR-145 hypermethyla-tion was negatively related with its expression. Conclusion MiR-145 hypermethylation is closely related with dif-ferentiation stage in NSCLC tissues. MiR-145 hypermethylation may be a potential biomarker for estimating NSCLC differentiation stage.

Helicobacter pylori Eradication Modulates Aberrant CpG Island Hypermethylation in Gastric Carcinogenesis / 대한소화기학회지

BACKGROUND/AIMS: Helicobacter pylori infection induces aberrant DNA methylation in gastric mucosa. We evaluated the long-term effect of H. pylori eradication on promotor CpG island hypermethylation in gastric carcinogenesis. METHODS: H. pylori-positive patients with gastric adenoma or early gastric cancer who underwent endoscopic resection were enrolled. According to H. pylori eradication after endoscopic resection, the participants were randomly assigned to H. pylori eradication or non-eradication group. H. pylori-negative gastric mucosa from normal participants provided the normal control. CpG island hypermethylation of tumor-related genes (p16, CDH1, and RUNX-3) was evaluated by quantitative MethyLight assay in non-tumorous gastric mucosa. The gene methylation rate and median values of hypermethylation were compared after one year by H. pylori status. RESULTS: In H. pylori-positive patients, hypermethylation of p16 was found in 80.6%, of CDH1 in 80.6%, and of RUNX-3 in 48.4%. This is significantly higher than normal control (p16, 10%; CDH1, 44%; RUNX-3, 16%) (p<0.05). In the H. pylori eradication group, methylation rates of p16 and CDH1 decreased in 58.1% and 61.3% of the patients, and the median values of hypermethylation were significantly lower at one year compared with the non-eradication group. However, RUNX-3 hypermethylation did not differ significantly at one year after H. pylori eradication. The non-eradication group hypermethylation did not change after one year. CONCLUSIONS: H. pylori infection was associated with promotor hypermethylation of genes in gastric carcinogenesis, and H. pylori eradication might reverse p16 and CDH1 hypermethylation.

Airway epithelial cell-derived insulin-like growth factor-1 triggers skewed CD8 +T cell polarization / 中国药理学通报

Aim To investigate the effects of airway epithelial cell-derived insulin-like growth factor-1 (IGF1) on CD8 +T cell polarization. Methods Hu-man airway epithelial cell line, RPMI2650 cells, was cultured in the presence of a mice allergen, Der p1, for 72 h. IGF1 expression was checked with quantita-tive RT-PCR and Western blot. Der p1-primed RP-MI2650 cells, recombinant IGF1 and anti-IGF1 anti-body was cocultured respectively with CD8 + T cells, which were activated by anti-CD3/CD8 Ab. Apoptotic cells frequency was calculated with flow cytometry. The alteration of p53 gene hypermethylation in CD8 + T cells elicited by Der p1-primed airway epithelial cell and IGF1 was plotted. Results Both mRNA(23. 1%± 5. 2% vs 5. 2% ± 2. 3%, P < 0. 01 ) and protein (33. 4 ± 6. 4 vs 9. 2 ± 4. 6, P <0. 01 ) expression of IGF1 in RPMI2650 cells markedly increased after ex-posure to Der p1 . The increase of apoptotic CD3/CD28 Ab-activated CD8 + T cells was abolished by the pres-ence of Derp1-primed epithelial cells ( 41. 7% ± 8. 2%vs 5. 2% ± 1. 8%, P <0. 01 ) . The results were con-firmed by the addition of recombinant IGF1 . Anti-IGF1 antibody abolished the effect of the epithelial cells. Derp1-primed epithelial cells inhibited p53 gene mR-NA( 29. 1% ± 5. 9% vs 16. 2% ± 4. 3%, P <0. 01 ) and protein ( 63. 3 ± 8. 9 vs 26. 9 ± 5. 6 , P <0. 01 ) ex-pression. Anti-IGF1 antibody abolished the effect. Re-combinant IGF1 promoted CD8 + T cells′p53 gene hy-permethylation. Conclusion Der p1 induces RP-MI2650 cells to produce IGF1 , and this factor prevents CD8 + T cell apoptosis by inducing p53 gene hyperm-ethylation.

Hipermetilación del gen supresor de tumores p53 en pacientes pediátricos con leucemia linfoblástica aguda / Hypermethylation of tumor suppressor gene p53 in Chilean pediatrics patients under 15 years with acute lymphoblastic leukemia

La leucemia linfoblástica aguda (LLA) es la neoplasia maligna hematooncólogica más frecuente en pacientes pediátricos contando hasta 75% de las leucemias y 32-35% del total de cánceres infantiles. Aunque la LLA es considerada una enfermedad con base genética, es cada vez más evidente que alteraciones epigenéticas desempeñan un rol central en su patogénia y progresión. La hipermetilación de regiones promotoras de genes es asociada con la pérdida de función génica. El gen supresor de tumores p53 (GST), es uno de los principales genes en el ciclo celular y apoptosis. El objetivo de este trabajo fue determinar el estado de metilación en la región del promotor-exón 1 del GST p53 y la asociación con la supervivencia en menores de 15 años con LLA. Se analizaron 40 pacientes provenientes de la Región de la Araucanía-Chile. La hipermetilación del p53 se determinó combinando enzimas de restricción sensibles a metilación (HpaII y EcoR II) y reacción en cadena de la polimerasa. Los resultados indicaron que 15/40 casos (37,5%) presentaron hipermetilación. Se encontró una diferencia estadística en la supervivencia según estado de metilación de p53 en el grupo de niñas (p=0,02). Considerando el total de pacientes, una tendencia a mejor supervivencia cuando los recuentos de leucocitos fueron <30.000/mm3 (p=0,08). Se encontró frecuentemente hipermetilado el gen p53 en la región del promotor-exon1. Esto indicaría que la hipermetilación del GST p53 puede ser un evento importante en la patogénesis de la LLA.

Acute lymphoblastic leukemia (ALL) is the most common hematology oncology malignancy in pediatric patients counting up to 75% of leukemias and 32­35% of all childhood cancers. Although ALL is considered a disease with a genetic basis, it is increasingly clear that epigenetic alterations play a central role in the pathogenesis and work was to determine the methylation status in promoter-exon1 of the TSG-p53 and association with survival in children under 15 years with ALL. In our study 40 patients from the Araucanía Region, Chile were analyzed. Hypermethylation of p53 was determined by combining restriction enzymes sensitive to methylation (HpaII and EcoR II) and polymerase chain reaction. Results indicated that 15/40 cases (37.5%) showed hypermethylation. Statistical difference was found in survival according to p53 methylation status in the girls group (p=0.02). Considering all patients, there was a trend to improved survival when leukocyte counts were <30.000/ul (p=0.08). We found the p53 gene frequently hypermethylated in the promoter-exon1 region. This would indicate that TSG p53 hypermethylation may be an important event in the pathogenesis of ALL.

Promoter hypermethylation patterns of P16, DAPK and MGMT in Oral Squamous Cell Carcinoma: A systematic review and meta-analysis.

Background: Oral squamous cell carcinoma (OSCC) is a common cancer world‑wide that is highly lethal due to its recurrence and metastasis. Methylation is a common epigenetic mechanism that leads to gene silencing in tumors and could be a useful biomarker in OSCC. The prevalence of P16, death‑associated protein kinase (DAPK) and O6‑methylguanine‑DNA‑methyltransferase (MGMT) promoter hypermethylation in OSCC has been evaluated for several years while the results remain controversial. Objective: The aim of this systematic review is to critically analyze and perform a meta‑analysis on the various studies in the literature that have reported the promoter hypermethylation of P16, DAPK and MGMT genes in OSCC. Search Strategy: Articles were searched and selected through PubMed. Hand search from the relevant journals was also performed. Articles were reviewed and analyzed. Results: The estimated prevalence of P16 methylation was 43%, DAPK methylation was 39.7% and MGMT methylation was 39.8%. Heterogeneity in methylation prevalences and correlations with the clinical outcomes of the disease prevailed in various studies. Conclusion: We can conclude from our systematic review that a higher prevalence of methylation of P16, DAPK and MGMT occur in OSCC. Further studies are required to substantiate the role of methylation of P16, DAPK and MGMT as a marker in OSCC.

Pathogenesis and Management of Serrated Polyps: Current Status and Future Directions

Hyperplastic or serrated polyps were once believed to have little to no clinical significance. A subset of these polyps are now considered to be precursors to colorectal cancers (CRC) in the serrated pathway that may account for at least 15% of all tumors. The serrated pathway is distinct from the two other CRC pathways and involves an epigenetic hypermethylation mechanism of CpG islands within promoter regions of tumor suppressor genes. This process results in the formation of CpG island methylator phenotype tumors. Serrated polyps are divided into hyperplastic polyps, sessile serrated adenomas/polyps (SSA/Ps), and traditional serrated adenomas (TSAs). The SSA/P and the TSA have the potential for dysplasia and subsequent malignant transformation. The SSA/Ps are more common and are more likely to be flat than TSAs. Their flat morphology may make them difficult to detect and thus explain the variation in detection rates among endoscopists. Challenges for endoscopists also include the difficulty in pathological interpretation as well surveillance of these lesions. Furthermore, serrated polyps may be inadequately resected by endoscopists. Thus, it is not surprising that the serrated pathway has been linked with interval cancers. This review will provide the physician or clinician with the knowledge to manage patients with serrated polyps.

Clinical study on expression and methylation of SOX17 gene in chronic myeloid leukemia / 实用医学杂志

Objective To investigate the expression level and promoter methylation of SOX17 gene and the clinical correlations in Chinese patients with chronic myeloid leukemia ( CML ) . Methods The levels of SOX17 expression and methylation were detected by RQ-PCR and RQ-MSP. Results SOX17 expression level was significantly lower in CML compared with 30 controls (P=0.001). The area under the receiver operating characteristic (ROC) curve (AUC) was 0.748 to differentiate CML from control (P=0.001). There was a trend of correlation between SOX17 expression and bcr/abl transcript (r = 0.439,P = 0.068) in CML patients. Hypermethylation of SOX17 promoter was detected in 3 (4%) CML patients, however, there was no difference as compared with 32 controls. In our study, SOX17 hypermethylation was not corrected with its expression. Conclusion Decreased SOX17 expression is a common molecular event in CML and may be considered as an available biomarker to diagnose CML. Dysregulated SOX17 is not caused by promoter hypermethylation in CML.

Epigenetic regulation of androgen receptors in prostate cancer / 中国肿瘤临床

The androgen receptor (AR), a nuclear hormone and transcription factor, is the most therapeutic relevant target in pros-tate cancer (PCa) and in the castration-resistant prostate cancer (CRPC). Significant efforts have been focused on understanding the mechanisms involved in the development and progression of CRPC. Recent work has revealed the importance of epigenetic events in-cluding the regulation of AR signaling by methylation, acetylation, and non-coding RNA in the tumorigenesis and development of PCa. We summarize recent findings on the mechanisms of epigenetic regulation of AR signaling in PCa.

Perfil de metilación de genes supresores de tumores APAF1, ASSP1, p73 y FHIT en pacientes con leucemia linfoblástica aguda infantil / Detection of hypermethylation in tumor suppressor genes APAF1, ASSP1, p73 and FHIT in childhood acute lymphoblastic leukemia

La leucemia linfoblástica aguda (LLA), es la neoplasia mas frecuente en la población infantil. Se manifiesta por una perdida de diferenciación de progenitores linfoides produciendo un aumento de células inmaduras. La hipermetilación en la región promotora de genes supresores de tumores (GST) puede producir un silenciamiento génico que le proporciona a la célula leucémica una ventaja proliferativa o la previene de la apoptosis. Se estudia el estado de hipermetilación de 4 GST involucrados en la apoptosis: APAF1, ASPP1, p73 y FHIT y su asociación con la sobrevida de pacientes menores de 15 años con diagnóstico de LLA. Se analizaron 38 muestras de médula ósea mediante modificación con bisulfito del ADN y reacción en cadena de la polimerasa especifica de metilación (MSP). El rango de edad al diagnóstico fue de 10 meses a 13,8 años. La sobrevida global fue de 69 por ciento a los 5 años. El 81,5 por ciento de los pacientes tuvo al menos un gen hipermetilado. La frecuencia de metilación observada fue: APAF1 68,4 por ciento, FHIT 56,4 por ciento, p73 42 por ciento y ASPP1 18,4 por ciento. La asociación entre hipermetilación y grupo <5 años y 5 años fue: Global p=0,20, APAF1 p=0,03, FHIT p=0,51, p73 p=0,51 y ASPP1 p=0.67. Las curvas de sobrevida se calcularon según frecuencia de hipermetilación de cada gen: APAF1 p=0,05, FHIT p=0,31, p73 p=0,98 y ASPP1 p=0,82. La alta frecuencia de hipermetilación obtenida reafirma la participación de la metilación en la región promotora de GST en la patogénesis de la LLA. La hipermetilación del gen APAF1 fue muy frecuente y se asoció significativamente a la sobrevida del grupo de estudio, mostrando a este gen como un factor predictivo de mal pronostico en pacientes con LLA.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. It is manifested by a loss of differentiation of lymphoid progenitors, producing an increase of immature cells. Hypermethylation in promoter region of tumor suppressor genes (GST) may produce a gene silencing that provides a leukemic cell a proliferative advantage or prevent apoptosis. We studied the hypermethylation status of 4 GST involved in apoptosis: APAF1, ASPP1, p73 and FHIT and its association with survival of patients <15 years diagnosed with ALL. We analyzed 38 samples of bone marrow by DNA bisulfite modification and chain reaction methylation-specific polymerase (MSP). The mean age at diagnosis was 10 months to 13.8 years. Overall survival was 69 percent at 5 years. 81.5 percent of patients had at least one hypermethylated gene. The frequency observed was: APAF1 68.4 percent, 56.4 percent FHIT, p73 ASPP1 42 percent and 18.4 percent. The association between hypermethylation and group <5 years and 5 years was: Global p = 0.20, APAF1 p = 0.03, FHIT p = 0.51, p73 p = 0.51, ASPP1 p = 0.67. Survival curves were calculated by frequency of hypermethylation of each gene: APAF1 p = 0.05, p = 0.31 FHIT, p73 p = 0.98 and ASPP1 p = 0.82. The high frequency of hypermethylation obtained confirms enrollment of methylation in the promoter region of GST in the pathogenesis of ALL. APAF1 gene hypermethylation was very frequent and was significantly associated with survival in the study group, showing this gene as a predictor of poor prognosis in patients with ALL.

Research progress of gene changes in gastric cancer / 肿瘤研究与临床

Gastric cancer is one of the leading causes of cancer mortality in the world.The development and progression of gastric cancer is attributed to a number of genetic and epigenetic alterations of oncogene and tumor suppress gene.

Quantitative Analysis of Cancer-associated Gene Methylation Connected to Risk Factors in Korean Colorectal Cancer Patients / 예방의학회지

OBJECTIVES: The purpose of this paper was to elucidate the potential methylation levels of adjacent normal and cancer tissues by comparing them with normal colorectal tissues, and to describe the correlations between the methylation and clinical parameters in Korean colorectal cancer (CRC) patients. METHODS: Hypermethylation profiles of nine genes (RASSF1, APC, p16INK4a, Twist1, E-cadherin, TIMP3, Smad4, COX2, and ABCB1) were examined with 100 sets of cancer tissues and 14 normal colorectal tissues. We determined the hypermethylation at a given level by a percent of methylation ratio value of 10 using quantitative methylation real-time polymerase chain reaction. RESULTS: Nine genes' hypermethylation levels in Korean CRC patient tissues were increased more higher than normal colorectal tissues. However, the amounts of p16INK4a and E-cadherin gene hypermethylation in normal and CRC tissues were not significantly different nor did TIMP3 gene hypermethylation in adjacent normal and cancer tissues differ significantly. The hypermethylation of TIMP3, E-cadherin, ABCB1, and COX2 genes among other genes were abundantly found in normal colorectal tissues. The hypermethylation of nine genes' methylation in cancer tissues was not significantly associated with any clinical parameters. In Cohen's kappa test, it was moderately observed that RASSF1 was related with E-cadherin, and Smad4 with ABCB1 and COX2. CONCLUSIONS: This study provides evidence for different hypermethylation patterns of cancer-associated genes in normal and CRC tissues, which may serve as useful information on CRC cancer progression.

Genetic factors in the pathogenesis of gastroesophageal reflux disease.

Multiple factors play a role in the pathogenesis of gastroesophageal reflux disease (GERD). Two landmark studies showing higher concordance of disease in monozygotic than dizygotic twin pairs suggested the role of host genetic factors in its pathogenesis. Recent studies have shown that genetic polymorphism in genes influencing host’s inflammatory response, drug metabolism, cell cycle regulation, xenobiotic pathways, DNA repair, mutagenesis, esophageal sensory function and gene silencing are associated with risk of GERD and its sequelae—Barrett’s esophagus and esophageal adenocarcinoma. However, more studies on larger sample size are needed before reaching a definite conclusion on the role of an individual gene.

The Overexpression of Histone Deacetylase 1 and Its Relationship with p16INK4a Gene Hypermethylation in Pulmonary Squamous Cell Carcinoma and Adenocarcinoma

BACKGROUND: DNA methylation and histone modification are dynamically linked in the epigenetic control of gene silencing and they play an important role in tumorigenesis. METHODS: To evaluate the role of histone deacetylase 1 (HDAC1) in the development of lung cancer and the relationship between a HDAC1 overexpression and p16INK4a hypermethylation, we performed immunohistochemical staining for HDAC1 in 76 lung cancer specimens (39 squamous cell carcinomas and 37 adenocarcinomas) that had been previously evaluated for their p16INK4a methylation status by real-time quantitative polymerase chain reaction. RESULTS: A HDAC1 overexpression (>50% of HDAC1 immunoreactive cells) was detected in 65 (85.5%) out of the 76 cases and it was more frequently seen in the squamous cell carcinomas (97.4%) than in the adenocarcinomas (73.0%) (p=0.002). The incidence of HDAC1 overexpression tended to be higher in the heavy smokers with more than 20 pack-years (p=0.067). Although there was no statistical significance, the frequency of p16INK4a hypermethylation in the cases with a HDAC1 overexpression (27.7%) tended to be higher than that in the cases without a HDAC1 overexpression (9.0%) (p=0.175). CONCLUSIONS: A HDAC1 overexpression might be involved in lung carcinogenesis, and especially in a subgroup of smoking and squamous cell carcinoma patients, and a HDAC1 overexpression may be associated with p16INK4a hypermethylation.