ABSTRACT
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.
Subject(s)
Humans , Cyclin-Dependent Kinases , DNA Methylation , Epigenomics , Gene Expression , Hematologic Neoplasms , Leukemia, Myeloid, Acute , Leukemia, Promyelocytic, Acute , Leukocytosis , Methylation , Polymerase Chain Reaction , Prognosis , Prospective Studies , Recurrence , Reverse Transcriptase Polymerase Chain Reaction , RNA, MessengerABSTRACT
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.
Subject(s)
Humans , Cyclin-Dependent Kinases , DNA Methylation , Epigenomics , Gene Expression , Hematologic Neoplasms , Leukemia, Myeloid, Acute , Leukemia, Promyelocytic, Acute , Leukocytosis , Methylation , Polymerase Chain Reaction , Prognosis , Prospective Studies , Recurrence , Reverse Transcriptase Polymerase Chain Reaction , RNA, MessengerABSTRACT
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.
Subject(s)
Carcinoma, Squamous Cell/analysis , Death-Associated Protein Kinases/metabolism , Genes, p16 , Genes, Reporter , Humans , MethylationABSTRACT
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.
ABSTRACT
OBJECTIVE: This study was to investigate the status of hypermethylation and loss of heterozygosity (LOH) in chromosome 3p tumor-suppressor gene for cervical carcinoma. METHODS: We examined the promoter methylation status of the chromosome 3p gene, fragile histidine triad (FHIT), in 37 samples of cervical squamous cell carcinoma and corresponding noncancerous tissues using a methylation-specific polymerase chain reaction. We also analyzed the 37 paired samples for LOH at two loci on chromosome 3p. RESULTS: Promoter hypermethylation in FHIT was detected in 24% of tumors, whereas no hypermethylation was detected in the corresponding noncancerous tissues. LOH in the regions of FHIT was observed in 10% of informative cases. There were no correlations between LOH and promoter hypermethylation for the gene. FHIT hypermethylation was associated with small tumors and, when adjusted for tumor size, correlated significantly with more frequent lymph node metastasis. CONCLUSION: Promoter hypermethylation and LOH of FHIT gene may play a role in cervical carcinogenesis. In addition, hypermethylation of FHIT may be associated with the status (aggressiveness) of cervical carcinoma.
Subject(s)
Female , Carcinogenesis , Carcinoma, Squamous Cell , Cervix Uteri , Histidine , Loss of Heterozygosity , Lymph Nodes , Methylation , Neoplasm Metastasis , Polymerase Chain ReactionABSTRACT
BACKGROUND: The aberrant promoter hypermethylation of p16(INK4a), as a tumor suppressor gene, is contributory factor to non-small cell lung cancer(NSCLC). However, its potential diagnostic impact of lung cancer is unclear. This study measured the level of p16(INK4a) promoter hypermethylation in the sputum and blood, and compared this with the level measured in the tissue obtained from NSCLC and pulmonary inflammation. METHODS: Of the patients who visited the Our Lady of Mercy Hospital in Incheon, Korea for an evaluation of a lung mass and underwent blood, sputum, and tissue tests, 23patients (18 NSCLC, 5 pulmonary inflammation) were enrolled in this study. DNA was extracted from each sample and the level of p16(INK4a) methylation was determined using methylation-specific polymerase chain reaction. RESULTS: p16(INK4a) methylation of the blood was observed in 88.9% (16 of 18) and 20.0% (1 of 5) of NSCLC and from pulmonary inflammation samples, respectively (P=0.008). Methylation of the sputum was observed in 83.3% (10 of 12) 80.0% (4 of 5) of NSCLC and pulmonary inflammation samples, respectively (P=1.00). Among the 8 NSCLC tissue samples, methylation changes were detected in 75.0% of samples (6 cases). Four out of seven tissue samples (57.1%) showed concordance, being methylated in both the blood and sputum. CONCLUSIONS: There was a higher level of p16(INK4a) methylation of the blood from NSCLC patients than from pulmonary inflammation. The tissue showed a high concordance with the blood in the NSCLC samples. These findings suggest that p16(INK4a) promoter hypermethylation of the blood can used to discriminate between NSCLC and pulmonary inflammation.
Subject(s)
Humans , Carcinoma, Non-Small-Cell Lung , Cyclin-Dependent Kinase Inhibitor p16 , DNA , Genes, Tumor Suppressor , Korea , Lung , Lung Neoplasms , Methylation , Pneumonia , Polymerase Chain Reaction , SputumABSTRACT
Background : PTEN, located on chromosome 10q23.31, is a novel tumor suppressor gene. In the sporadic breast cancers, the incidence of the loss of heterozygosity of PTEN is approximately 10% to 40%, but the incidence of intragenic mutation of PTEN is less than 1%. To as- sess the role of the PTEN in the invasive ductal breast cancer, we studied the frequency of the loss of PTEN expression, its correlation with the commonly used prognostic factors of the breast cancer and with PTEN promoter hypermethylation status. Methods : Immunohistochemical staining with an anti-PTEN protein antibody was performed on the paraffin-embedded breast tissues from 129 women with a diagnosis of invasive ductal carcinoma. Methylation specific PCR was performed to detect hypermethylation in the PTEN gene on the 28 cases with the loss of PTEN expression. Results : Sixty-two (48%) of 129 breast tumors had the loss of PTEN expression. The loss of PTEN expression was correlated with lymph node metastasis and stage, and there was a near-significant correlation with the tumor size. PTEN promoter hypermethylation was found in five (18%) out of 28 patients. Conclusion : These results suggest that the loss of PTEN expression might play a role in the progression of the breast cancer and that the aberrant promoter methylation is one of the silencing mechanisms of PTEN.