Aberrant Genes Promoter Methylation in Neural Crest-Derived Tumors

2012 ◽  
Vol 27 (4) ◽  
pp. 389-394 ◽  
Author(s):  
Annamaria La Torre ◽  
Lucia Anna Muscarella ◽  
Paola Parrella ◽  
Teresa Balsamo ◽  
Michele Bisceglia ◽  
...  
Keyword(s):  
Small Bowel ◽  
Neural Crest ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Cpg Islands ◽  
Aberrant Methylation ◽  
Tumor Type ◽  
Epigenetic Landscape ◽  
Molecular Biomarker

Disturbances in the epigenetic landscape by aberrant methylation of CpG islands can lead to inactivation of cancer-related genes in solid tumors. We analyzed the promoter methylation status of 6 genes previously reported as cancer-specific methylated (MCAM, SSBP2, NISCH, B4GALT1, KIF1A and RASSF1A) in 38 neural crest-derived tumors by quantitative methylation-specific real-time PCR (QMSP). The results demonstrated that the determination of the methylation status of RASSF1A is able to distinguish between normal and tumor samples in cutaneous melanomas, lung carcinoids and small bowel carcinoids. MCAM methylation levels were significantly higher in lung carcinoids tumors (p=0.001), suggesting that this alteration may represent a molecular biomarker in this tumor type.

Title: Promoter Methylation of Selected Genes and Response to Azacitidine (AZ) Therapy in Patients with Non-BCR-ABL Myeloproliferative Disorders (MPDs)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4625-4625
Author(s):  
Nicholas Achille ◽  
Laura Michaelis ◽  
Scott E. Smith ◽  
Eliza Germano ◽  
Nancy J. Zeleznik-Le ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Promoter Methylation ◽  
Research Funding ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Cpg Islands ◽  
Myeloproliferative Disorders ◽  
Response To Treatment ◽  
Promoter Regions ◽  
Days Of Therapy

Abstract Abstract 4625 Background: Gene silencing via methylation of CpG islands in the promoter regions of many genes but specifically of APAF1, p15INK4B, p16INK4A, RARB, and CDH1 appears to play a role in pathogenesis of myeloid malignancies. Azacitidine (AZ) causes demethylation by inhibiting DNA methyltransferase and has already been shown to be an effective therapy for myelodysplastic syndromes. The demethylation induced by AZ is detectable in about 48 hours and increases significantly after 5 days of therapy. After that, the effect tends to plateau. Methods: We initiated a Phase 2 study of patients with non-BCR-ABL MPDs to determine clinical response to AZ therapy and correlate it with promoter DNA methylation and gene re-expression. The protocol was approved by the institutional IRB. Patients received AZ 75mg/m2 s/c for days 1–7 and repeated every 28 days for a minimum of 4 cycles. Responders were allowed to continue treatment until disease progression. Pretreatment and D 7 peripheral blood samples were analyzed for promoter methylation status and expression of the 5 genes mentioned above. Bisulfite conversion of DNA was followed by quantitative PCR using primers specific for methylated or for unmethylated promoter regions. For gene re-expression analysis, quantitative RT-PCR was performed with RNA isolated from the same patient samples and the same time points as the DNA methylation analyses. Results: Seven patients were enrolled before the study closed due to lack of accrual. The diagnoses were: Myelofibrosis (MF) 4, essential thrombocythemia 1, unclassified MPD with dysplasia 2. One patient with MF and one with unclassified MPD responded, the latter with normalization of marrow karyotype. Both responses were accompanied by significant decrease in APAF1 promoter methylation and surprisingly, an increase in promoter methylation of RARB. In three of the non-responders, APAF1 methylation increased. In patients with decreased Apaf1 methylation, a statistically significant increase in mRNA expression was observed. Conclusions: Within its limitations, this small trial shows that the methylation status of selected genes, particularly of APAF1 and RARB (inversely) is associated with response to treatment with azacitidine in patients with MPDs. In non-responders, Apaf1 methylation appears to increase. A larger study will be necessary to confirm these preliminary observations. Disclosures: Smith: Seattle Genetics, Inc.: Research Funding; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Spectrum: Consultancy; GSK: Speakers Bureau. Nand:Celgene Corporation: Research Funding.

Cohesin RAD21 Gene Promoter Methylation in Patients with Chronic Lymphocytic Leukemia

2018 ◽  
Vol 154 (3) ◽  
pp. 126-131 ◽  
Author(s):  
Agapi Ioannidou ◽  
Sophia Zachaki ◽  
Maria Karakosta ◽  
Aggeliki Daraki ◽  
Paraskevi Roussou ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Promoter Methylation ◽  
Chromosomal Abnormalities ◽  
Methylation Status ◽  
Cpg Islands ◽  
Gene Promoter ◽  
Common Type ◽  
Lymphocytic Leukemia ◽  
Cytogenetic Abnormalities ◽  
Epigenetic Processes

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults and is characterized by the presence of specific cytogenetic abnormalities. CLL research has been focused on epigenetic processes like gene promoter methylation of CpG islands. In the present study, the methylation status of the RAD21 gene is studied and associated with cytogenetic findings in CLL patients in order to investigate its possible implication in CLL pathogenesis and the formation of CLL chromosomal abnormalities.

Gene-Specific Methylation: Potential Markers for Colorectal Cancer

2009 ◽  
Vol 24 (1) ◽  
pp. 57-62 ◽  
Author(s):  
Jyothi S. Prabhu ◽  
Aruna Korlimarla ◽  
Arindam Banerjee ◽  
Shivangi Wani ◽  
K Payal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Polymerase Chain Reaction ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Epigenetic Mechanism ◽  
Aberrant Methylation ◽  
Chain Reaction ◽  
Promoter Methylation Status ◽  
Polymerase Chain

Purpose Aberrant methylation of the promoter region is associated with silencing of many genes in neoplasia. CpG island methylation is an epigenetic mechanism for transcriptional silencing that occurs at various stages of colon tumorigenesis. In this study, we tested the promoter methylation and expression of seven genes from various pathways of DNA repair, apoptosis and inflammation, i.e., sFRP1, MLH1, RASSF1A, CDA, v-fgr, LYN-B, and TNFR10d. Method The genes were analyzed by quantitative polymerase chain reaction for the level of gene expression. The promoter methylation status of the genes was studied by methylation-specific polymerase chain reaction. Result The correlation of promoter methylation status with suppressed gene expression patterns suggested a potential role for the silencing these genes in colon cancer progression. Conclusion Promoter methylations of the studied genes could be explored as promising biomarkers for new diagnostic, prognostic and therapeutic targets of colorectal cancer.

Aberrant methylation of tumour suppressor genes WT1, GATA5 and PAX5 in hepatocellular carcinoma

2016 ◽  
Vol 54 (12) ◽  
Author(s):  
Martin Mžik ◽  
Marcela Chmelařová ◽  
Stanislav John ◽  
Jan Laco ◽  
Ondřej Slabý ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Promoter Methylation ◽  
Mrna Level ◽  
Methylation Status ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
Aberrant Methylation ◽  
Suppressor Genes ◽  
Tissue Samples ◽  
Differentially Methylated Genes

AbstractBackground:Aberrant hypermethylation of tumour suppressor genes (TSGs) occurring in hepatocellular carcinoma (HCC) could provide a mean of molecular characterisation of this cancer. The aim of this study was to investigate promoter methylation and gene expression of selected TSGs in HCC to identify candidate genes for further validation as potential biomarkers.Methods:Methylation-specific multiplex ligation-dependent probe amplification method was used to measure the methylation status of 25 TSGs in 49 HCC samples and 36 corresponding non-cancerous liver tissue samples. Relative expression of the differentially methylated genes was assessed at the mRNA level using quantitative PCR.Results:We observed a significantly higher methylation in genesConclusions:HCC evince aberrant promoter methylation of

scholarly journals Epigenetic Inactivation of Protocadherin 10 by Methylation in Colorectal Cancer

2020 ◽  
Author(s):  
Mohammad Amin Kerachian ◽  
Sahar Tavakolian ◽  
Matineh Barati Bagherabad ◽  
Dor Mohammad Kordi-Tamandani ◽  
Mohammad Reza Abbaszadegan
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Cpg Islands ◽  
High Specificity ◽  
Suppressor Gene ◽  
Potential Candidate ◽  
Critical Function ◽  
Normal Tissues

Aberrant promoter methylation of CpG islands of tumor-suppressor genes has been recognized as one of the important tumor markers for cancer detection. The aim of this study was to investigate the promoter methylation status of protocadherin 10 (PCDH10), a tumor suppressor gene, in Iranian colorectal cancer (CRC) patients. Cancerous and the adjacent normal tissues obtained from 38 CRC patients were used to assess the methylation status of PCDH10 with Methylation Specific PCR, in addition, to study the expression level of this gene by quantitative PCR. The relationship between hypermethylation and the demographic characteristics of these patients was analyzed. The promoter methylation level of PCDH10 was statistically different between tumoral and normal tissues in CRC patients. Twenty-seven out of 38 patients showed hypermethylation with a sensitivity of 73% and a specificity of 97%. PCDH10 expression decreased in 15 cases (46%) as 16 cases (50 %) showed overexpression and 1 case (4%) had no changes. Not a significant association was reported between PCDH10 hypermethylation and the clinicopathological characteristics (P>0.05). Our results indicated that PCDH10 methylation has a critical function in CRC, with a nearly elevated sensitivity and a high specificity in the Iranian population, qualify it as a potential candidate biomarker. © 2019 Tehran University of Medical Sciences. All rights reserved. Acta Med Iran 2019;57(8):472-477.

Abstract 36: FCGR2A Promoter Methylation and Risks for IVIG Unresponsiveness in Kawasaki Disease

Circulation ◽  
2015 ◽  
Vol 131 (suppl_2) ◽  
Author(s):  
Ho-Chang Kuo ◽  
Kai-Sheng Hsieh ◽  
Wei-Chiao Chang ◽  
Keyword(s):  
Kawasaki Disease ◽  
Promoter Methylation ◽  
Systemic Vasculitis ◽  
Methylation Status ◽  
Cpg Islands ◽  
Gene Promoter ◽  
Ivig Therapy ◽  
Ivig Treatment ◽  
Fc Fragment ◽  
Cpg Sites

Kawasaki disease (KD) is characterized by pediatric systemic vasculitis of an unknown cause and the Fc Fragment of IgG, Low Affinity IIa, Receptor ( FCGR2A ) gene was reported to involve in increasing susceptibility of KD. Because DNA methylation is one of the epigenetic mechanisms that control gene expression, we hypothesized that methylation status of CpG islands in FCGR2A promoter predisposes an individual to Kawasaki disease. We recruited 36 KD patients and 24 healthy subjects with informed consents. And eleven potential methylation loci within the targeted promoter region (chr1:161474603-161475102) of Fc Fragment of IgG, Low Affinity IIa, Receptor were selected for investigation. Methylation at the CpG sites G, H and J displayed a strongly associations with KD, whereas CpG sites B,C,E,F,H,J and K were found to be correlated with non-responsive to IVIG treatment. In addition, CpG sites G, J and K were predicted as the significant transcription factor binding site for NF-kB, Myc-Max and SP2 respectively. Our study reports a significant association between the promoter methylation of FCGR2A , susceptibility of Kawasaki disease and therapeutic outcomes of IVIG treatment. The methylation levels of CpG sites of FCGR2A gene promoter may be an important marker for optimizing IVIG therapy.

Methylation profiling in acute myeloid leukemia

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2823-2829 ◽  
Author(s):  
Minoru Toyota ◽  
Kenneth J. Kopecky ◽  
Mutsumi-Ohe Toyota ◽  
Kam-Wing Jair ◽  
Cheryl L. Willman ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cpg Island ◽  
Methylation Status ◽  
Cpg Islands ◽  
Correlation Coefficients ◽  
Aberrant Methylation ◽  
Independent Events ◽  
Methylation Defects ◽  
Acute Myeloid

Abstract Aberrant methylation of multiple CpG islands has been described in acute myeloid leukemia (AML), but it is not known whether these are independent events or whether they reflect specific methylation defects in a subset of cases. To study this issue, the methylation status of 14 promoter-associated CpG islands was analyzed in 36 cases of AML previously characterized for estrogen-receptor methylation (ERM). Cases with methylation density of 10% or greater were considered positive. Seventeen cases (47%) were ERM+ while 19 cases were ERM−. Hypermethylation of any of the following,p15, p16, CACNA1G,MINT1, MINT2, MDR1,THBS1, and PTC1 (2 promoters), was relatively infrequent (6% to 31% of patients). For each of these CpG islands, the methylation density was positively correlated with ERM density (rank order correlation coefficients, 0.32-0.59; 2-tailedP ≤ .058 for each gene). Hypermethylation ofMYOD1, PITX2, GPR37, andSDC4 was frequently found in AML (47% to 64% of patients). For each of these genes as well, methylation density was positively correlated with ERM density (correlation coefficients 0.43 to 0.69, P ≤ .0087 for each gene). MLH1 was unmethylated in all cases. Hypermethylation of p15,MDR1, and SDC4 correlated with reduced levels of expression. There was an inverse correlation between age and the number of genes methylated (P = .0030). It was concluded that CpG-island methylation in AML results from methylation defects in subsets of cases. These results have potential implications for the classification and prognosis of AML and for the identification of patients who may benefit from treatment with methylation inhibitors.

scholarly journals Hypermethylation of the p15INK4B Gene in Myelodysplastic Syndromes

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1403-1409 ◽  
Author(s):  
Toshiki Uchida ◽  
Tomohiro Kinoshita ◽  
Hirokazu Nagai ◽  
Yohsuke Nakahara ◽  
Hidehiko Saito ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Malignant Tumors ◽  
Cpg Island ◽  
Methylation Status ◽  
Cpg Islands ◽  
Hematologic Malignancies ◽  
Genetic Alterations ◽  
Refractory Anemia ◽  
Aberrant Methylation ◽  
Cyclin Dependent Kinase Inhibitor

Previous studies have shown that the cyclin-dependent kinase inhibitor (CDKI) genes p15INK4B and p16INK4A are frequently inactivated by genetic alterations in many malignant tumors and that they are candidate tumor-suppressor genes. Although genetic alterations in these genes may be limited to lymphoid malignancies, it has been reported that their inactivation by aberrant methylation of 5′ CpG islands may be involved in various hematologic malignancies. In this study, we investigated the p15INK4B and p16INK4A genes to clarify their roles in the pathogenesis of myelodysplastic syndrome (MDS). Southern blotting analysis showed no gross genetic alterations in either of these genes. However, hypermethylation of the 5′ CpG island of the p15INK4B gene occurred frequently in patients with MDS (16/32 [50%]). Interestingly, the p15INK4B gene was frequently methylated in patients with high-risk MDS (refractory anemia with excess blasts [RAEB], RAEB in transformation [RAEB-t], and overt leukemia evolved from MDS; 14/18 [78%]) compared with patients with low-risk MDS (refractory anemia [RA] and refractory anemia with ring sideroblast [RARS]; 1/12 [8%]). Furthermore, methylation status of the p15INK4B gene was progressed with the development of MDS in most patients examined. In contrast, none of the MDS patients showed apparent hypermethylation of the p16INK4A gene. These results suggest that hypermethylation of the p15INK4B gene is involved in the pathogenesis of MDS and is one of the important late events during the development of MDS.

Alteration of the p53 and Rb tumor suppressor pathways by p16/INK4a and p14/ARF promoter methylation and loss of protein expression in recurrent and nonrecurrent meningiomas.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2064-2064
Author(s):  
Juan Carlos Martinez ◽  
Santiago Ropero ◽  
Concepcion Mateos ◽  
Maria DEL VAL Toledo ◽  
Rafael Samaniego ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Protein Expression ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Cpg Islands ◽  
Similar Proportion ◽  
Surgical Removal ◽  
Low Grade ◽  
Epigenetic Changes

2064 Background: Promoter methylation inactivates tumor suppressor genes (TSG). The INK4a/ARF locus encodes p16INKa and p14ARF cell cycle regulatory proteins, which control Rb and p53 TSG pathways. Most meningiomas are slow growing tumors, but in spite of complete surgical removal, the recurrence rate at 5 years is 5%, rising to 19% in long-term follow-up. However, there are no markers predictive of this evolution. Epigenetic changes in low-grade meningiomas have not been previously addressed. To get insights into the possible role of p16INK4a and p14ARF TSG alterations in grade 1 meningiomas, we study the methylation status and protein expression of these genes in 140 specimens of meningiomas: 29 nonrecurrent and 57 recurrent in one, two or three times. Methods: Methylation specific PCR and bisulfate modification followed by bisulfate genomic sequencing of CpG islands and staining with p16INKa and p14ARF antibodies (Ab’s). Results: Our data show p16INK4a and p14ARF methylation in 43.4% and14.2% meningiomas respectively. Methylation of p16INK4a is found in a similar proportion in non-recurrent meningiomas (37.9%) and the first biopsy of recurrent cases (38.8%) and increases to a 52.3% in successive biopsies of recurrent cases. Methylation of p14ARF occurs in 13.8% of nonrecurrent vs. 9.6% recurrent meningiomas (first biopsy) and 19.6% of successive recurrent meningiomas. Loss of p16INK4a and p14ARF protein expression was shown in 52.7% and 18.6% of meningiomas respectively. p16INK4a and p14ARF methylation was associated with loss of protein expression in 54.7% and 18.8% of meningiomas. Loss of p16INK4a and p14ARF expression was associated with unmethylated promoters in 52.9% and 17.6% of cases respectively. Conclusions: Epigenetic changes of p16INK4a and p14ARF genes and loss of protein expression leading to Rb and p53 TSG pathways alterations, may have a pathogenic role in human meningiomas. Loss of p16INK4a and p14ARF protein expression associated with unmethylated promoters, could be due to loss of heterozigosity or gen mutation. Increase of p16INK4a and p14ARF methylation along the following biopsies of recurrent cases suggests a possible role of methylation in tumor progression.

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