scholarly journals Analysis of smad4 gene promoter methylation in pancreatic and endometrial cancers

2017 ◽  
Vol 23 (2) ◽  
pp. 17-19
Author(s):  
Aleksandra Nikolic ◽  
Filip Opincal ◽  
Momcilo Ristanovic ◽  
Jovanka Trifunovic ◽  
Srbislav Knezevic ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Methylation Status ◽  
Gene Promoter ◽  
Promoter Hypermethylation ◽  
Surgical Removal ◽  
Smad4 Gene ◽  
Frequent Event ◽  
Cancer Types ◽  
Endometrial Cancers ◽  
Tumor Types

Background. Promoter hypermethylation of the SMAD4 gene has been registered in some cancer types, but in general doesn?t appear to be a frequent event in carcinogenesis. However, only a few published studies deal with this topic and not many cancer types have been analyzed. The aim of this study was to establish SMAD4 gene promoter methylation status in pancreatic and endometrial cancers. Methods. Patients included in the study (62 subjects) were diagnosed and surgically treated at the University of Belgrade, Clinical Center of Serbia. Patients with pancreatic carcinoma (17 subjects) underwent surgical removal of the pancreatic adenocarcinoma at the First Surgical Clinic, while the patients with endometrial carcinoma (45 subjects) underwent hysterectomy with adnexectomy at the Institute for Gynecology and Obstetrics. Extraction of DNA from fresh tissue samples was performed and the methylation status of the SMAD4 gene promoter was studied by a previously designed PCR-based HpaII and MspI restriction enzyme assay. The resulting PCR products were analyzed by electrophoresis in 2% agarose gels. Results. Neither of the analyzed samples was found to be hypermethylated. Conclusion. This is the first report on SMAD4 methylation status in pancreatic and endometrial tumor specimens, and supports the viewpoint that SMAD4 hypermethylation is not a common event in malignant tumors. Nevertheless, promoter hypermethylation remains a candidate mechanism for SMAD4 inactivation in malignant tissue as a potential cause of decreased or lost SMAD4 expression in certain tumor types, and should be further investigated in different tumor types and larger cohorts of patients.

scholarly journals DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment

2018 ◽  
Vol 179 (3) ◽  
pp. 153-160 ◽  
Author(s):  
E B Conemans ◽  
L Lodewijk ◽  
C B Moelans ◽  
G J A Offerhaus ◽  
C R C Pieterman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Tumor Suppressor ◽  
Promoter Methylation ◽  
Tumor Suppressor Genes ◽  
Gene Promoter ◽  
Pancreatic Neuroendocrine Tumor ◽  
Promoter Hypermethylation ◽  
Suppressor Gene ◽  
Suppressor Genes ◽  
Frequent Event

ObjectiveEpigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs.Design and methodsMethylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN1-related (n = 61) and sporadic (n = 34) PanNETs. Differences in cumulative methylation index (CMI), individual methylation percentages and frequency of promoter hypermethylation between subgroups were analyzed.ResultsWe found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876,P = 0.207) was the same in MEN1-related and sporadic PanNETs. We found higher methylation percentages ofCASP8in MEN1-related PanNETs (median: 59% vs 16.5%,P = 0.002). In MEN1-related non-functioning PanNETs, the CMI was higher in larger PanNETs (>2 cm) (median: 969.5 vs 838.5;P = 0.021) and in PanNETs with liver metastases (median: 1036 vs 869;P = 0.013). Hypermethylation ofMGMT2was more frequent in non-functioning PanNETs compared to insulinomas (median: 44.7% vs 8.3%;P = 0.022). Hypermethylation of the Von Hippel–Lindau gene promoter was observed in one MEN1-related PanNET and was associated with loss of protein expression.ConclusionPromoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.

Assesment of SOX-17 gene promoter hypermethylation in hepatocellular carcinoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15063-e15063
Author(s):  
Leonidas Chelis ◽  
Ioanna Balgouranidou ◽  
Triantafyllia Koukaki ◽  
Prodromos Michailidis ◽  
Evagelos Christakidis ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Performance Status ◽  
Methylation Status ◽  
Gene Promoter ◽  
Staging System ◽  
Promoter Hypermethylation ◽  
Suppressor Gene ◽  
Impaired Performance ◽  
Promoter Sequences ◽  
Frequent Event

e15063 Background: SRY-box containing gene 17 (SOX-17) is implicated in the WNT/β-catenin pathway and acts as a tumor suppressor gene inhibiting the transcription of activated β-catenin. WNT oncogene plays a crucial role in liver carcinogenesis and has been shown to correlate with poor survival and aggressive behavior in hepatocellular carcinoma (HCC). Silencing of SOX-17 gene through promoter hypermethylation results in WNT overexpression. Tumor-related cell free DNA (cfDNA), circulating in the blood of cancer patients can be used for the detection of methylation status of several genes. Therefore, we examined SOX-17 methylation in the blood of HCC patients and correlated it with the outcome. Methods: Patients diagnosed with HCC were eligible. cfDNA from 87 patients (N=87) was isolated from 200 μL serum before any treatment. After DNA extraction, all samples were subjected to a sodium bisulfite conversion reaction. Methylation specific polymerase reaction (MSP) for SOX17 promoter methylation was performed using specific primer pairs for both the methylated and unmethylated promoter sequences. Results: According to BCLC staging system, our patients were staged as A=5 (5.6%), B=15 (17.2%), C=67 (77%) respectively. SOX-17 methylation was detected in 58 (66.7%) patients while 29 (33.3%) had a non-methylated gene. The methylated form of the gene was significantly correlated with an impaired performance status (PS) of 2-4 (p=0.021) and with extrahepatic spread of the disease (p=0.036). No correlation was detected for stage, Child-Pough score of cirrhosis, or underlying cause of HCC. The overall survival (OS) was 14 months for the non-methylated and 5 months for the methylated gene, respectively (p= 0.0062). Sixty three patients received sorafenib as 1st line treatment. The OS was 15 months for patients with the non-methylated and 6 months for patients with the methylated gene, respectively (p= 0.012). In the multivariate analysis for OS, SOX-17 methylation status along with PS remained significant (p=0.04) Conclusions: Assessment of SOX-17 promoter hypermethylation in the peripheral blood is feasible. SOX-17 gene methylation is a frequent event in HCC and seems to correlate with a poorer outcome.

scholarly journals Genome-wide analysis identifies critical DNA methylations within NTRKs genes in colorectal cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Zijian Chen ◽  
Zenghong Huang ◽  
Yanxin Luo ◽  
Qi Zou ◽  
Liangliang Bai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Promoter Methylation ◽  
Expression Profiles ◽  
Methylation Status ◽  
Gene Promoter ◽  
Normal Mucosa ◽  
Suppressor Gene ◽  
Survival Outcome ◽  
Prognostic Models

Abstract Background Neurotrophic tropomyosin receptor kinases (NTRKs) are a gene family function as oncogene or tumor suppressor gene in distinct cancers. We aimed to investigate the methylation and expression profiles and prognostic value of NTRKs gene in colorectal cancer (CRC). Methods An analysis of DNA methylation and expression profiles in CRC patients was performed to explore the critical methylations within NTRKs genes. The methylation marker was validated in a retrospectively collected cohort of 229 CRC patients and tested in other tumor types from TCGA. DNA methylation status was determined by quantitative methylation-specific PCR (QMSP). Results The profiles in six CRC cohorts showed that NTRKs gene promoter was more frequently methylated in CRC compared to normal mucosa, which was associated with suppressed gene expression. We identified a specific methylated region within NTRK3 promoter targeted by cg27034819 and cg11525479 that best predicted survival outcome in CRC. NTRK3 promoter methylation showed independently predictive value for survival outcome in the validation cohort (P = 0.004, HR 2.688, 95% CI [1.355, 5.333]). Based on this, a nomogram predicting survival outcome was developed with a C-index of 0.705. Furthermore, the addition of NTRK3 promoter methylation improved the performance of currently-used prognostic model (AIC: 516.49 vs 513.91; LR: 39.06 vs 43.64, P = 0.032). Finally, NTRK3 promoter methylation also predicted survival in other tumors, including pancreatic cancer, glioblastoma and stomach adenocarcinoma. Conclusions This study highlights the essential value of NTRK3 methylation in prognostic evaluation and the potential to improve current prognostic models in CRC and other tumors.

P16 Methylation Is an Early Event in Cervical Carcinogenesis

2011 ◽  
Vol 21 (3) ◽  
pp. 452-456 ◽  
Author(s):  
Lee-Wen Huang ◽  
Hun-Shan Pan ◽  
Yu-Hung Lin ◽  
Kok-Min Seow ◽  
Heng-Ju Chen ◽  
...  
Keyword(s):  
Cervical Intraepithelial Neoplasia ◽  
Promoter Methylation ◽  
Intraepithelial Neoplasia ◽  
Promoter Hypermethylation ◽  
Early Event ◽  
Low Grade ◽  
Neoplastic Progression ◽  
Frequent Event ◽  
Significant Difference ◽  
Low Grade Dysplasia

BackgroundAberrant gene promoter methylation is a critical event in tumorigenesis. The aim of this study was to explore the promoter hypermethylation of p16 and DAPK1 during the progression of cervical precancerous lesions.MethodsA series of 98 cervical neoplasms (72 cervical intraepithelial neoplasia and 26 cervical carcinomas) were evaluated. The promoter methylation status of p16 and DAPK1 was assessed from cervical scrapings by methylation-specific polymerase chain reaction.ResultsFor p16, the frequency of promoter hypermethylation showed an increasing trend from normal to dysplastic to invasive squamous cancer specimens, and this increase reached statistical significance (P < 0.0001). However, there was no significant difference in the promoter methylation state of DAPK1 with regard to the various grades of cervical lesions (P = 0.077). Specifically, methylation of p16 was a frequent event in the cervical carcinoma samples, and these figures were statistically significant compared with the normal and cervical intraepithelial neoplasia I cases (P = 0.015 and P = 0.021, respectively).ConclusionsThese results imply that promoter hypermethylation of p16 occurs at an early stage of cervical neoplastic progression. This early event may play an initiating role in the malignant transformation of low-grade dysplasia into high-grade dysplasia and invasive carcinoma. We suggest that aberrant promoter methylation of p16 may serve as a useful biomarker during the follow-up of low-grade dysplasia.

scholarly journals Analysis of SEPT9 Gene Promoter Methylation Status in Esophageal Squamous Cell Carcinoma

2020 ◽  
Author(s):  
Aida Mirza Aghasi ◽  
Saied Ghorbian
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Gene Promoter ◽  
Sodium Metabisulfite ◽  
Significant Difference ◽  
Cancer Tissues

Introduction: The changes in the level of SEPT9 gene promoter methylation can contribute to the formation of esophageal squamous cell carcinoma. The aim of this study was to evaluate the level of changes in the level of SEPT9 gene promoter methylation in the esophageal squamous cell carcinoma. Methods: In the present case-control study, we collected 75 paraffin blocks of esophageal cancer tissues and 75 paraffin blocks healthy tissues, which were referred to the Noor-E-Nejat and Tabriz International Hospitals during 2013-2017. After DNA extraction and treatment with sodium metabisulfite, the changes of SEPT9 gene promoter methylation assessed using high resolution melting (HRM) technique. The data were analyzed by SPSS 22 and Chi-square test. Results: Our findings did not show a statistically significant difference between the changes of SEPT9 gene promoter methylation in cancer tissues compared to the healthy tissues (P=0.106). Conclusion: This study shows that SEPT9 gene promoter methylation cannot contribute to the esophageal squamous cell carcinoma cancerogenesis.  

Prognostic role of promoter hypermethylation of death-associated protein (DAP) kinase and p16 genes in early-stage non-small cell lung cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7216-7216
Author(s):  
C. Lu ◽  
I. Wistuba ◽  
X. Zhou ◽  
B. N. Bekele ◽  
J. B. Putnam ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Early Stage ◽  
Methylation Status ◽  
Promoter Hypermethylation ◽  
Stage I ◽  
Prognostic Role ◽  
Early Stage Nsclc ◽  
Dap Kinase ◽  
Nsclc Patients

7216 Background: Promoter hypermethylation is an epigenetic mechanism of gene silencing commonly observed in malignancies. Prior studies suggest that hypermethylation of DAP kinase and p16, genes involved in apoptosis and cell cycle regulation, respectively, are associated with poorer survival in NSCLC patients. In this study we investigate the prognostic role of DAP kinase and p16 promoter hypermethylation in a large cohort of early-stage NSCLC patients. Methods: Pathologic stage I and II NSCLC patients who underwent complete surgical resection between 1/97 and 12/01 at our institution and did not receive adjuvant therapy were identified. Formalin-fixed, paraffin-embedded tissue blocks were retrieved, and p16 and DAP kinase promoter methylation status was determined by methylation specific PCR. Two-sided statistical analyses were performed to determine associations between methylation status, clinicopathologic characteristics, and survival. Results: DAP kinase and p16 methylation status was observed in 36.3% (97 of 267) and 36.4% (95 of 261) cases, respectively. Subject characteristics: 55% female, 77% former/current smokers, 81% stage I, 19% stage II, 61% adenocarcinoma, 29% squamous carcinoma, 63% performance status (PS) 0, 37% PS 1,93% < 5% weight loss. Recurrent NSCLC and death occurred in 21.3% and 38% of cases, respectively. No significant associations were observed between DAP kinase methylation status and subject characteristics. P16 methylation was associated with moderate/high grade (p = 0.03). A higher frequency of p16 methylation was observed in ever vs never smokers (39% vs 28%, p = 0.17). Preliminary analyses do not demonstrate significant associations between methylation status and overall survival (p16 p = 0.13; DAP kinase p = 0.56) or disease-free survival (p16 p = 0.36; DAP kinase p = 0.71). Conclusions: In this relatively large cohort of early-stage NSCLC patients, we did not detect significant associations between p16 and DAP kinase promoter methylation and clinical outcome. Further subset analyses stratified by gender and histology will be performed. The prognostic role of these biomarkers in NSCLC remains unclear. No significant financial relationships to disclose.

ATM gene analysis in neuroblastoma: A report from the COG

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10058-10058
Author(s):  
F. Gumy-Pause ◽  
H. Ozsahin ◽  
M. Khoshbeen-Boudal ◽  
B. Pardo ◽  
D. Betts ◽  
...  
Keyword(s):  
Rare Variants ◽  
Direct Sequencing ◽  
Methylation Status ◽  
Promoter Hypermethylation ◽  
Pathogenic Mutation ◽  
Allelic Frequency ◽  
Chromosome 11 ◽  
Frequent Event ◽  
Pcr Products ◽  
Atm Gene

10058 Background: Neuroblastoma (NB) is the most common malignant disease of infancy and accounts for approximately 8% of all childhood cancers. The clinical hallmark of this tumor is the marked variability in prognosis depending of the age, stage, and biological characteristics. There is evidence to suggest that the long arm of chromosome 11 (11q) plays a role in NB biology. The ATM gene is located at 11q22–23 and hereditary mutations of this gene cause ataxia-telangiectasia, a recessive disorder associated with a high incidence of neoplasia. The aim of this project was to determine the prevalence of ATM gene mutation and ATM methylation status in 50 NB samples. Methods: Following DNA extraction, PCR products of the 65 exons of the ATM gene and its promoter were screened by DHPLC. This screening was also performed on DNA from 60 blood donors. Alterations detected were analyzed by direct sequencing. Direct and indirect criteria were used to classify the observed nucleotide alterations as mutation (if pathogenic), rare variant (if the allelic frequency in controls was < or = 1%), variant (1.1–2.4%) or polymorphism (> or = 2.5%). The ATM methylation status was analyzed by MS-MLPA (Methylation-Specific Multiplex Ligation-dependent Probe Amplification). Results: Except polymorphisms, 17 different sequence alterations were found in 17 NB samples (34%). Ten of these 17 alterations, found in 11 NB (22%), were rare variants (RV). In 5 NB (10%), RV were found homozygous. At the same time, we found 20 different sequence alterations in 19 controls (32%). Sixteen of these 20 alterations were RV and one was a heterozygous pathogenic mutation. These 17 alterations concern 15 controls (25%). No homozygous RV was found in controls. We found no evidence of ATM promoter hypermethylation in the 48 NB samples analyzed. Conclusions: We found no difference in ATMvariant and RV frequency between NB and control samples. However, as ATM deletion is a frequent event in NB, we found a high frequency of homozygous RV (10%). At present, we are completing this study by screening ATMlarge genomic deletion/duplication using MLPA. Finally, our observations indicate that epigenetic ATM silencing by methylation is uncommon in neuroblastoma. No significant financial relationships to disclose.

Predicting gene promoter methylation in lung tumors through examination of sputum and serum

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7208-7208
Author(s):  
S. A. Belinsky ◽  
M. Grimes ◽  
D. Johnson ◽  
D. Levy ◽  
J. Schiller
Keyword(s):  
Lung Cancer ◽  
Cell Function ◽  
Biological Fluids ◽  
Methylation Status ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Gene Promoter ◽  
Promoter Hypermethylation ◽  
Phase Iii ◽  
Advanced Lung Cancer

7208 Background: Personalized medicine may be a key approach in improving survival for advanced lung cancer. Success for this approach is seen with the response of cancer patients with an activating mutation within the epidermal growth factor receptor to the growth fact inhibitor, gefitinib. Genes involved in all types of normal cell function are targeted for inactivation by promoter hypermethylation during lung cancer development. This makes gene-specific promoter hypermethylation an attractive target for novel treatment strategies. One obstacle to targeted therapy is accessibility of tissue from peripheral tumors for methylation analysis. The purpose of this study was to determine the predictive power of sputum and serum to detect NSCLC through analysis for methylation of genes in these fluids. Methods: Tissue, serum, and sputum were obtained from 72 stage III NSCLC patients participating in a Phase III trial of Carboplatin, Paclitaxel and Radiotherapy, With or Without Thalidomide (ECOG 3598). Methylation specific PCR assessed methylation of the p16, MGMT, DAPK, RASSF1A, PAX5-α, PAX5-β, H-cadherin, and GATA5 genes. Results: At least one gene was methylated in 89% of tumors. Prevalence for methylation ranged from 15–47% and did not differ between gender. Methylation of ≥ 3 genes was seen in ∼50% of tumors. The agreement between sputum or serum in classifying methylation status of any gene in the tumor ranged from 54– 69%. The reduced sensitivity was presumably due in part to absence of tumor DNA in the biological fluids of methylation positive tumors. Logistic regression models revealed 3.1 (CI, 1.2, 8.2) and 4.2 (1.1, 16.1) increased odds for methylation of the p16 and MGMT gene, respectively in tumors if the serum or sputum was positive for methylation. The effect of tumor histology for predicting methylation using sputum and serum is being examined. Conclusion: These studies demonstrate for genes such as p16 and MGMT the possibility of interrogating biological fluids to predict for methylation in the primary tumor. (Supported by CA-89551). No significant financial relationships to disclose.

Sign in / Sign up

Export Citation Format

Share Document