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

2021 ◽  
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.

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.

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

2020 ◽  
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 to evaluate prognosis risk, improve current prognostic models and the potential to guide treatment in CRC and other tumors.

scholarly journals Downregulation ofDLC-1Gene by Promoter Methylation during Primary Colorectal Cancer Progression

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Haixia Peng ◽  
Feng Long ◽  
Zhiyuan Wu ◽  
Yimin Chu ◽  
Ji Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Promoter Methylation ◽  
High Resolution Melting ◽  
Methylation Status ◽  
Normal Mucosa ◽  
Suppressor Gene ◽  
Transformation Process ◽  
Melting Analysis ◽  
Colorectal Cancer Progression

Purpose.DLC-1is a tumor suppressor gene frequently silenced in human cancers. However, the pathogenicity ofDLC-1epigenetic silencing in the mucosa-adenoma-carcinoma transformation process of colorectal cancer (CRC) has not been studied.Methods. Promoter methylation status ofDLC-1was evaluated in 4 human CRC cell lines, 48 normal mucosa, 57 adenomas, and 80 CRC tissues with methylation-sensitive high-resolution melting analysis (MS-HRMA), while the mRNA expression was examined by qPCR. HRMA was utilized to detect theKRAScodon 12, 13 andBRAFV600Emutations.Results. Partial (1%–10%) and extensive (10%–100%)DLC-1promoter methylations were observed in 10% and 0% of normal mucosa, 46% and 14% of adenomas, and 60% and 36% of CRCs, respectively. The promoter methylation ofDLC-1was related with the reduction of gene expression and the advanced Duke’s stages (Stage C and D).DLC-1promoter methylation andKRASmutations are common concurrent pathological alternations.Conclusions. Epigenetic alternation plays a key role in the transcriptional silencing ofDLC-1. It is also an independent risk factor related to the carcinogenesis of colorectal tumors and spans over its pathogenesis process. Therefore,DLC-1promoter methylation quantitation may have a promising significance in the evaluation and management of CRC patients.

scholarly journals Enhanced CXCR4 Expression Associates with Increased Gene Body 5-Hydroxymethylcytosine Modification but not Decreased Promoter Methylation in Colorectal Cancer

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 539 ◽  
Author(s):  
Alexei J. Stuckel ◽  
Wei Zhang ◽  
Xu Zhang ◽  
Shuai Zeng ◽  
Urszula Dougherty ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Cell Lines ◽  
Promoter Methylation ◽  
Cpg Island ◽  
Methylation Status ◽  
Cxcr4 Expression ◽  
Normal Colonic Mucosa ◽  
Gene Body ◽  
Expression Levels

In colorectal cancer (CRC), upregulation of the C-X-C motif chemokine receptor 4 (CXCR4) is correlated with metastasis and poor prognosis, highlighting the need to further elucidate CXCR4’s regulation in CRC. For the first time, DNA methylation and 5-hydroxymethylcytosine aberrations were investigated to better understand the epigenetic regulation of CXCR4 in CRC. CXCR4 expression levels were measured using qPCR and immunoblotting in normal colon tissues, primary colon cancer tissues and CRC cell lines. Publicly available RNA-seq and methylation data from The Cancer Genome Atlas (TCGA) were extracted from tumors from CRC patients. The DNA methylation status spanning CXCR4 gene was evaluated using combined bisulfite restriction analysis (COBRA). The methylation status in the CXCR4 gene body was analyzed using previously performed nano-hmC-seal data from colon cancers and adjacent normal colonic mucosa. CXCR4 expression levels were significantly increased in tumor stromal cells and in tumor colonocytes, compared to matched cell types from adjacent normal-appearing mucosa. CXCR4 promoter methylation was detected in a minority of colorectal tumors in the TCGA. The CpG island of the CXCR4 promoter showed increased methylation in three of four CRC cell lines. CXCR4 protein expression differences were also notable between microsatellite stable (MSS) and microsatellite instable (MSI) tumor cell lines. While differential methylation was not detected in CXCR4, enrichment of 5-hydroxymethylcytosine (5hmC) in CXCR4 gene bodies in CRC was observed compared to adjacent mucosa.

scholarly journals Epigenetic Deregulation of Protocadherin PCDHGC3 in Pheochromocytomas/Paragangliomas Associated With SDHB Mutations

2019 ◽  
Vol 104 (11) ◽  
pp. 5673-5692 ◽  
Author(s):  
Cristóbal Bernardo-Castiñeira ◽  
Nuria Valdés ◽  
Lucía Celada ◽  
Andrés San José Martinez ◽  
I Sáenz-de-Santa-María ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Promoter Methylation ◽  
De Novo ◽  
Gene Promoter ◽  
Gene Clusters ◽  
Suppressor Gene ◽  
Migration And Invasion ◽  
Primary Tumors ◽  
Genome Wide ◽  
Potential Biomarker

Abstract Context SDHB mutations are found in an increasing number of neoplasms, most notably in paragangliomas and pheochromocytomas (PPGLs). SDHB-PPGLs are slow-growing tumors, but ∼50% of them may develop metastasis. The molecular basis of metastasis in these tumors is a long-standing and unresolved problem. Thus, a better understanding of the biology of metastasis is needed. Objective This study aimed to identify gene methylation changes relevant for metastatic SDHB-PPGLs. Design We performed genome-wide profiling of DNA methylation in diverse clinical and genetic PPGL subtypes, and validated protocadherin γ-C3 (PCDHGC3) gene promoter methylation in metastatic SDHB-PPGLs. Results We define an epigenetic landscape specific for metastatic SDHB-PPGLs. DNA methylation levels were found significantly higher in metastatic SDHB-PPGLs than in SDHB-PPGLs without metastases. One such change included long-range de novo methylation of the PCDHA, PCDHB, and PCDHG gene clusters. High levels of PCDHGC3 promoter methylation were validated in primary metastatic SDHB-PPGLs, it was found amplified in the corresponding metastases, and it was significantly correlated with PCDHGC3 reduced expression. Interestingly, this epigenetic alteration could be detected in primary tumors that developed metastasis several years later. We also show that PCDHGC3 down regulation engages metastasis-initiating capabilities by promoting cell proliferation, migration, and invasion. Conclusions Our data provide a map of the DNA methylome episignature specific to an SDHB-mutated cancer and establish PCDHGC3 as a putative suppressor gene and a potential biomarker to identify patients with SDHB-mutated cancer at high risk of metastasis who might benefit from future targeted therapies.

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.

scholarly journals Frequent RASSF1A tumour suppressor gene promoter methylation in Wilms' tumour and colorectal cancer

Oncogene ◽  
2002 ◽  
Vol 21 (47) ◽  
pp. 7277-7282 ◽  
Author(s):  
Kate J Wagner ◽  
Wendy N Cooper ◽  
Richard G Grundy ◽  
Germaine Caldwell ◽  
Carolyn Jones ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Promoter Methylation ◽  
Gene Promoter ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Wilms Tumour

Protein Expression of p15 and p21 Plays an Unfavorable Prognostic Role in Adult Acute Lymphoblastic Leukemia (ALL) Patients Independently of Their Gene Promoter Methylation Status.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2802-2802
Author(s):  
Fabiana De Cave ◽  
Maria Teresa Petrucci ◽  
Chiara Gregorj ◽  
Maria Rosaria Ricciardi ◽  
Samantha Decandia ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Protein Expression ◽  
Promoter Methylation ◽  
Lymphoblastic Leukemia ◽  
Methylation Status ◽  
Gene Promoter ◽  
Prognostic Role ◽  
P21 Protein ◽  
Promoter Methylation Status ◽  
P16 Protein

Abstract Epigenetic silencing of tumor suppressor (TS) genes is a hallmark in human leukemias, particularly through DNA methylation. Cyclin-dependent kinase inhibitors (CKI) are, among other genes, frequently found methylated in their promoter region. This epigenetic modification has been described also in acute lymphoblastic leukemia (ALL). However, the relationship between aberrant DNA methylation and protein expression of TS genes has not yet been extensively evaluated in adult ALL series. The aim of this study was to analyze in primary cells from newly diagnosed adult ALL patients, uniformly treated according to the LAL2000 GIMEMA protocol, the promoter methylation status of p73, p21, p15 and p16, evaluating in addition the p21, p15 and p16 protein expression. The DNA methylation status of promoter regions was investigated, according to cell availability, using a widely accepted method based on bisulfite modification of DNA, followed by methylation-specific PCR assay (MSP). Protein expression was evaluated by Western blot. Normal peripheral blood lymphocytes, as already described, resulted unmethylated for p73, p21, p15 and p16, and did not express the p21, p15 and p16 proteins. In ALL patients, in contrast, only the p21 promoter region was found constantly unmethylated. The p15, p16 and p73 promoter genes were found methylated in 15/37 (40.5%), 8/43 (18.6%) and 9/36 (25%) patients, respectively. Only 2/23 cases (8.6%) resulted simultaneously methylated for p15, p16 and p73. The p21 and p15 protein expression was found in 28/85 (32.9%) and 44/85 cases (51.8%), respectively. The p16 protein, in contrast, was never expressed. The p16 methylation was associated with the T-ALL (P=0.005) phenotype and with higher white blood cell (WBC) counts (P=0.027). Resistance to spontaneous induction of apoptosis was significantly associated with p21 protein expression (P=0.019) and its co-expression with p15 (P=0.049). Achievement of CR was not influenced by gene methylation status, nor by single protein expression. Interestingly, the co-expression of p15 and p21 was associated with failure to induction treatment: only 6/63 (9.5%) patients co-expressing p15 and p21 obtained a CR (P=0.027). Multivariate analysis confirmed the unfavorable role of this protein co-expression (P=0.059) on CR achievement. In contrast, once patients achieved remission, p21 protein expression was associated with a prolonged DFS, as confirmed by multivariate analysis for DFS (P=0.039). In conclusion, p15 and p21 protein expression plays an unfavorable prognostic role in adult ALL patients independently of the p73, p21, p15 and p16 gene promoter methylation status.

Global DNA methylation and tumor suppressor gene promoter methylation and gastric cancer risk in an Omani Arab population

Epigenomics ◽  
2011 ◽  
Vol 3 (4) ◽  
pp. 417-429 ◽  
Author(s):  
Jennifer A Rusiecki ◽  
Maryam Al-Nabhani ◽  
Letizia Tarantini ◽  
Ligong Chen ◽  
Andrea Baccarelli ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Methylation ◽  
Tumor Suppressor ◽  
Cancer Risk ◽  
Promoter Methylation ◽  
Gene Promoter ◽  
Suppressor Gene ◽  
Global Dna Methylation ◽  
Gastric Cancer Risk ◽  
Arab Population

scholarly journals Synergic effect of diabetes mellitus and H. pylori infection on proliferation of cells via downregulating the expression of PTEN by hypermethylating its promoter region

2020 ◽  
Author(s):  
Huibin Lu ◽  
Xinwei Han ◽  
Jianzhuang Ren ◽  
Kewei Ren ◽  
Zongming Li ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Gastric Cancer ◽  
Dna Methylation ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Suppressor Gene ◽  
Tissue Samples ◽  
Tumor Tissues ◽  
Pten Mrna ◽  
H Pylori

Abstract Background It has been reported that CagA of H. pylori reduced the expression of PTEN by enhancing its promoter methylation. Furthermore, DM may also promote the methylation status of PTEN, a tumor suppressor gene in Gastric cancer. It is intriguing to explore whether DM may strengthen the tumorigenic effect of HP by promoting the methylation of PTEN promoter and whether the administration of metformin may reduce the risk of GC by suppressing the methylation of PTEN promoter. Methods Bisulfite sequencing PCR was performed to measure the DNA methylation of PTEN promoter in GC patients and HGC-27 cells treated under different conditions. Quantitative real-time PCR was carried out to measure the expression of PTEN mRNA. Immunohistochemistry and Western blot were used to evaluate the expression of PTEN protein. Immunofluorescence and flow cytometry were performed to analyze the apoptosis of GC tissue samples and HGC-27 cells treated under different conditions. MTT assay was carried out to examine the proliferation of HGC-27 cells. Results DNA methylation of PTEN promoter was synergetic enhanced by HP infection and Diabetes mellitus in patients with Gastric cancer. Accordingly, the expression of PTEN was suppressed in GC patients with HP infection and DM. Furthermore, cell apoptosis was decreased in GC patients with HP infection and DM. Metformin showed an apparent effect on maintaining CagA induced elevation of PTEN promoter methylation, thus attenuating the PTEN expression, increasing the proliferation and suppressing the apoptosis of HGC-27 cells. Conclusion In this study, we collected GC tumor tissues from GC patients with or without DM/HP to compare their PTEN methylation and expression while testing the effect of Metformin on the methylation of PTEN promoter. Our study provided evidence for the mechanism underlying the therapeutic role of Metformin in GC treatment.

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