scholarly journals Promoter Methylation of Tumor Suppressors in Thyroid Carci-noma: A Systematic Review

2021 ◽  
Author(s):  
Sara Sheikholeslami ◽  
Marjan Zarif -Yeganeh ◽  
Samaneh Farashi ◽  
Fereidoun Azizi ◽  
Sima Kheradmand Kia ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Thyroid Cancer ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Critical Role ◽  
Methylation Status ◽  
Exclusion Criteria ◽  
Suppressor Genes ◽  
Thyroid Malignancies ◽  
The Impact

Background: The tumor suppressor genes play a critical role in cellular and molecular mechanisms such as cell cycle processes, cell differentiation and apoptosis. Aberrant DNA methylation of tumor suppressor genes and subsequent gene expression changes have shown to be involved in the initiation and progression of various malignancies including thyroid malignancies. In this review, we investigated what is known about the impact of promoter hypermethylation on the key tumor suppressor genes known to be involved in cell growth and/or apoptosis of thyroid cancer. Methods: The most important databases were searched for research articles until June 2020 to identify reported tumor suppressor genes that are modulated by methylation modulation changes in thyroid carcinoma. Following the inclusion and exclusion criteria, 26 studies were reviewed using the full text to meet the inclusion and exclusion criteria. Results: The tumor suppressor genes reviewed here are suggestive biomarkers and potential targetable drugs. Inactivation of RASSF1A, DAPK1, SLCFA8, and TSHR through aberrant epigenetic methylation could activate BRAF/MEK/ERK kinase pathways with potential clinical implications in thyroid cancer patients. RARβ2 and RUNX3 could suppress cell cycle and induce apoptosis in malignant cells. TIMP3 and PTEN could prevent angiogenesis and invasion through PIP3 pathway and arrest VEFG activity. Conclusion: The methylation status of key genes in various types of thyroid malignancies could be used in early diagnosis as well as differentiation of malignant and benign thyroid. This is valuable in drug repurposing and discovering alternative treatments or preventions in thyroid cancer.

DNMT3A Mutations Are Connected with Lower DNA Methylation Levels and Numbers of Concurrently Hypermethylated Genes in AML Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4629-4629 ◽  
Author(s):  
Hana Hajkova ◽  
Jana Markova ◽  
Cedrik Haskovec ◽  
Jaroslav Cermak ◽  
Radka Petrbokova ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Healthy Donor ◽  
Hox Genes ◽  
Methylation Status ◽  
Wild Type ◽  
Suppressor Genes ◽  
The Impact ◽  
Hypermethylated Genes

Abstract Abstract 4629 Recently, mutations in DNA methyltransferase 3A (DNMT3A) have been found in patients with acute myeloid leukemia (AML) and have been confirmed to be connected with adverse clinical outcome. As DNMT3A plays direct role in the process of DNA methylation by adding methyl group to the cytosine residue of CpG dinucleotides, the question is obvious: What is the impact of DNMT3A mutations on DNA methylation levels? We examined 79 AML patients at diagnosis for the presence of aberrant DNA methylation of 12 tumor suppressor genes (TSG) (CDKN2B, CALCA, CDH1, ESR1, SOCS1, MYOD1, DAPK1, TIMP3, ICAM1, TERT, CTNNA1, EGR1) by methylation specific real-time PCR (MethyLight) and for mutations in the gene DNMT3A by direct sequencing. Next we studied methylation status of 24 HOX genes from all four clusters A-D using methylation-restriction endonucleases followed by RQ-PCR arrays in 10 AML samples compared to 4 healthy donor samples. Sequencing of cDNA between amino acids 300 and 930 revealed that 32 of 79 AML patients had DNMT3A mutation. The reason for higher DNMT3A mutation incidence in our patients’ cohort consists in preferential selection of AML patients with a higher percentage of probability of DNMT3A mutation (it means normal karyotype and mutations in NPM1, FLT3 and/or IDH1/2 genes). MethyLight assessment of 12 TSG showed subsequent frequencies of hypermethylation: CDKN2B (47%), CALCA (43%), CDH1 (22%), SOCS1 (24%), MYOD1 (18%), ESR1 (14%). The remaining 6 genes were weakly methylated in less than 10 % AML patients at diagnosis and were therefore excluded from further analysis. DNA methylation arrays revealed a set of differentially methylated HOX genes (n=12): 11 HOX genes were hypermethylated (HOXA4, HOXA6, HOXB13, HOXB3, HOXB4, HOXB7, HOXB8, HOXC8, HOXD10, HOXD11, HOXD3) and HOXA5 was hypomethylated compared to healthy donor samples. Comparing overall cumulative DNA methylation levels and numbers of simultaneously hypermethylated genes to mutational status of DNMT3A gene, we did observe lower levels of DNA methylation (P<0.0001) as well as displaying lower numbers of concurrently hypermethylated genes (P<0.0001) in patients with DNMT3a mutations. We observed the same trend also in DNA methylation levels of HOX genes when compared mutant (n=4) versus wild-type (n=6) DNMT3A patients. These results clearly show that numbers of simultaneously hypermethylated genes and DNA methylation levels of chosen tumor suppressor genes (TSG) as well as HOX genes differs between AML patients with wild type and mutant DNMT3A. This study is part of the COST Action BM0801 (EuGESMA) and is supported by NS10632-3/2009, OC10042 and IHBT00023736. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Promoter Methylation of Four Tumor Suppressor Genes in Human Papillary Thyroid Carcinoma

2019 ◽  
Vol 14 (4) ◽  
pp. 290-298 ◽  
Author(s):  
Fatemeh Khatami ◽  
Bagher Larijani ◽  
Ramin Heshmat ◽  
Shirzad Nasiri ◽  
Hiva Saffar ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Promoter Methylation ◽  
Tumor Suppressor Genes ◽  
Methylation Status ◽  
Common Type ◽  
P Value ◽  
Papillary Thyroid ◽  
Expression Change ◽  
Suppressor Genes ◽  
The Impact

Background & Objective: Papillary thyroid cancer (PTC) is considered to be the most common type of thyroid malignancies. Epigenetic alteration, in which the chromatin conformation and gene expression change without changing the sequence of DNA, can occur in some tumor suppressor genes and oncogenes. Methylation is the most common type of epigenetic alterations that can be an excellent indicator of PTC invasive behavior. Methods: In this research, we determined the promoter methylation status of four tumor suppressor genes (SLC5A8, RASSF1, MGMT, and DNMT1) and compared the results of 55 PTC cases with 40 goiter patients. For methylation, we used the methylation-sensitive high resolution melting (MS-HRM) assay technique. The resulting graphs of each run were compared with those of 0%, 50%, and 100% methylated controls. Results: Our data showed that the promoter methylation of SLC5A8, Ras association domain family member 1(RASSF1), and MGMT were significantly different between PTC tissue and goiter with P-value less than 0.05. The most significant differences were observed in RASSF1; 77.2% of hyper-methylated PTC patients versus 15.6% hyper-methylated goiter samples (P<0.001). Conclusion: RASSF1 promoter methylation can be a PTC genetic marker. RASSF1 promoter methylation is under the impact of the methyltransferase genes (DNMT1 and MGMT), protein expression, and promoter methylation.

Sleep quality and methylation status of selected tumor suppressor genes among nurses and midwives

2017 ◽  
Vol 35 (1) ◽  
pp. 122-131 ◽  
Author(s):  
Agnieszka Bukowska-Damska ◽  
Edyta Reszka ◽  
Pawel Kaluzny ◽  
Edyta Wieczorek ◽  
Monika Przybek ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Sleep Quality ◽  
Tumor Suppressor Genes ◽  
Methylation Status ◽  
Suppressor Genes ◽  
Nurses And Midwives

Association Between Cyclin D1 Polymorphism with CpG Island Promoter Methylation Status of Tumor Suppressor Genes in Gastric Cancer

2010 ◽  
Vol 55 (12) ◽  
pp. 3449-3457 ◽  
Author(s):  
Tomomitsu Tahara ◽  
Tomoyuki Shibata ◽  
Masakatsu Nakamura ◽  
Hiromi Yamashita ◽  
Daisuke Yoshioka ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Suppressor ◽  
Cyclin D1 ◽  
Promoter Methylation ◽  
Tumor Suppressor Genes ◽  
Cpg Island ◽  
Methylation Status ◽  
Suppressor Genes ◽  
Promoter Methylation Status

Methylation status of eight tumor suppressors in neuroendocrine pancreatic tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16197-e16197
Author(s):  
Oleg I. Kit ◽  
Vladimir S. Trifanov ◽  
Natalya N. Timoshkina ◽  
Dmitry Yu. Gvaldin ◽  
Milana Yu. Mesheryakova ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Methylation Status ◽  
Blood Levels ◽  
Malignant Neoplasms ◽  
Gene Promoters ◽  
Suppressor Genes ◽  
Healthy Donors ◽  
Pancreatic Net

e16197 Background: Aberrant DNA methylation is a characteristic feature of cancer, affecting gene expression and tumor phenotype. In this study, we quantified the methylation of promoters of eight tumor suppressor genes in pancreatic neuroendocrine tumors (Pan-NET). Methods: The method of pyrosequencing was used to quantity level (Met,%) of methylation of gene promoters - tumor suppressors AHRR, APC1A, DAPK, MGMT, MLH1, P16, RASSF1A, RUNX3 in tumor samples from 55 patients with pancreatic NET (G1-G3) and in the blood of 10 healthy donors. Met for each sample was calculated as the median methylation of CpG sites in triplicate. Results: Hypermethylation was observed for AHRR (75%), APC1A (25%), RASSF1A (30%). In contrast, DAPK, MGMT, MLH1, P16, RUNX3 had low methylation levels ( < 20%). The median of methylation in the blood of healthy donors for AHRR was 91% (76-98); for all other loci it did not exceed 6%. A high incidence of methylation in excess of blood levels in healthy donors was identified for RASSF1A (0.96); AHRR (0.75); MGMT (0.65); RUNX3 (0.41), APC1A (0.25). For tumor suppressor P16, only one case of increased methylation was recorded (Met = 15%), despite the fact that this phenomenon is not uncommon for NETs of other localizations. In 66% of pancreatic NET cases, hypermethylation of more than two promoters of tumor suppressor genes was noted. An association tendency was found between the presence of MEN1 mutations and the RASSF1A methylation level (p = 0.08). Correlation analysis revealed a significant level of negative association between changes in methylation of MLH1 and AHRR (p < 0.01); for the latter, the prognostic value of a high methylation status and a better prognosis for many malignant neoplasms were described. Conclusions: In the present study, significant methylation of the promoters of the APC1A, DAPK, MGMT, RASSF1A, and RUNX3 genes in well-differentiated pancreatic NETs was identified with a high frequency. At the same time, isolated cases of hypermethylation were noted for the well-known tumor suppressors MLH1 and P16.

Expression of tumor suppressor genes related to the cell cycle in endometrial cancer patients

2016 ◽  
Vol 61 (2) ◽  
pp. 317-324 ◽  
Author(s):  
Łukasz Witek ◽  
Tomasz Janikowski ◽  
Piotr Bodzek ◽  
Anita Olejek ◽  
Urszula Mazurek
Keyword(s):  
Cell Cycle ◽  
Endometrial Cancer ◽  
Tumor Suppressor ◽  
Cancer Patients ◽  
Tumor Suppressor Genes ◽  
Suppressor Genes

scholarly journals Inactivation of multiple tumor-suppressor genes involved in negative regulation of the cell cycle, MTS1/p16INK4A/CDKN2, MTS2/p15INK4B, p53, and Rb genes in primary lymphoid malignancies

Blood ◽  
1996 ◽  
Vol 87 (12) ◽  
pp. 4949-4958 ◽  
Author(s):  
A Hangaishi ◽  
S Ogawa ◽  
N Imamura ◽  
S Miyawaki ◽  
Y Miura ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Cell Cycle Control ◽  
Negative Regulators ◽  
Suppressor Genes ◽  
Multiple Tumor ◽  
Lymphoid Malignancies ◽  
Cell Cycle Machinery

It is now evident that the cell cycle machinery has a variety of elements negatively regulating cell cycle progression. However, among these negative regulators in cell cycle control, only 4 have been shown to be consistently involved in the development of human cancers as tumor suppressors: Rb (Retinoblastoma susceptibility protein), p53, and two recently identified cyclin-dependent kinase inhibitors, p16INK4A/MTS1 and p15INK4B/MTS2. Because there are functional interrelations among these negative regulators in the cell cycle machinery, it is particularly interesting to investigate the multiplicity of inactivations of these tumor suppressors in human cancers, including leukemias/lymphomas. To address this point, we examined inactivations of these four genes in primary lymphoid malignancies by Southern blot and polymerase chain reaction-single- strand conformation polymorphism analyses. We also analyzed Rb protein expression by Western blot analysis. The p16INK4A and p15INK4B genes were homozygously deleted in 45 and 42 of 230 lymphoid tumor specimens, respectively. Inactivations of the Rb and p53 genes were 27 of 91 and 9 of 173 specimens, respectively. Forty-one (45.1%) of 91 samples examined for inactivations of all four tumor suppressors had one or more abnormalities of these four tumor-suppressor genes, indicating that dysregulation of cell cycle control is important for tumor development. Statistical analysis of interrelations among impairments of these four genes indicated that inactivations of the individual tumor-suppressor genes might occur almost independently. In some patients, disruptions of multiple tumor-suppressor genes occurred; 4 cases with p16INK4A, p15INK4B, and Rb inactivations; 2 cases with p16INK4A, p15INK4B, and p53 inactivations; and 1 case with Rb and p53 inactivations. It is suggested that disruptions of multiple tumor suppressors in a tumor cell confer an additional growth advantage on the tumor.

Aberrant Gene Promoter Methylation of Tumor Suppressor Genes in Plasma Cell Disorders.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2487-2487
Author(s):  
Carmen Stanganelli ◽  
Jorge Arbelbide ◽  
Juliana Zimerman ◽  
Dorotea Beatriz Fantl ◽  
Claudia Corrado ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Peripheral Blood ◽  
Tumor Suppressor Genes ◽  
Methylation Status ◽  
Genetic Alterations ◽  
Negative Regulator ◽  
Epigenetic Mechanism ◽  
Gene Methylation ◽  
Suppressor Genes ◽  
Number Of Genes

Abstract There is increasing evidence that, in addition to genetic aberrations, epigenetic processes play a major role in carcinogenesis. Particularly, hypermethylation of CpG islands of the promoter regions of tumor suppressor genes (TSG) is now considered as an important epigenetic mechanism for gene inactivation. Multiple myeloma (MM) is characterized by neoplastic proliferation of monoclonal plasma cells. The natural course of disease may progress through monoclonal gammopathy of undetermined significance (MGUS) to MM. During this process, multiple genetic alterations are sequentially acquired and aberrant promoter hypermethylation might be one of the steps involved in this progression. In this study, we have evaluated methylation status of the following TSG: p15INK4b, p16INK4a, p14ARF, SOCS-1, p27KIP1, RASSF1A and p73 genes, in order to determine if they were involved in the evolution of MGUS to MM. Forty four MM (21 males; mean age 67.5 years; Durie-Salmon clinical stages: I: 20%, II:14% and III: 66%) and 21 MGUS patients (6 males; mean age 68 years) were study. All patients gave informed consent and the study was approved by the Ethics Committee of our Institution. Peripheral blood samples from 10 normal individuals and CpGenome Universal Methylated DNA (Chemicon International) were used as negative and positive controls, respectively. DNA was extracted from bone marrow cells of patients and peripheral blood lymphocytes of controls using phenol/chloroform method. Methylation status was performed using Methylation Specific PCR (MSP) technique. For statistical analysis, Student t and Fisher exact tests were used. The methylation index (MI; ratio between the number of genes methylated and the number of genes analyzed) was also calculated. SOCS-1 gene methylation was significantly more frequent in MM (52%) than in MGUS patients (14%) (p=0,006). Frequencies of methylation of p14ARF, p15INK4b, p16INK4a and RASSF1A were comparable in both entities: 29%, 32%, 7% and 2%, respectively, for MM; and 29%, 29%, 5% and 0%, respectively, for MGUS. TP73 gene showed a tendency of higher methylation in MM (45%) than in MGUS (33%). All patients lacked methylation at p27KIP1 gene. Whereas the percentage of MM with at least one gene methylated (84%) did not showed differences to that of MGUS (66%), the mean MI of MGUS was lower (0.16; range 0.14-0.43) than that of MM (0.24; range 0.14-0.71) (p&lt;0.05). None of the target genes were methylated in normal samples. No statistical significant correlation with clinical characteristics: gender, age, isotype, level of M-component, type of light chain, stage of the disease, haemoglobin, serum albumin level, calcium, β2 microglobulin and LDH, were observed. To our knowledge, this is the first report of methylation in MM and MGUS from Argentina. The similar frequency of p14ARF, p15INK4b, p16INK4a and RASSF1A gene methylation observed in MM and MGUS would suggest that they are probably not involved in the progression of MGUS. However, SOCS1 gene methylation was significantly more frequent in MM than in MGUS suggesting that methylation of this gene might be involved in clonal evolution of MGUS to MM. SOCS1 is a negative regulator of cytokine signaling, being important in normal lymphocyte development and differentiation. Silencing of SOCS1 may result in greater responsiveness to cytokines, which may favour the neoplastic development.

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