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 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 Restoring HOXD10 Exhibits Therapeutic Potential for Ameliorating Malignant Progression and 5-Fluorouracil Resistance in Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Weijie Pan ◽  
Kaijing Wang ◽  
Jiayong Li ◽  
Hanhua Li ◽  
Yuchan Cai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Therapeutic Potential ◽  
Methylation Status ◽  
Suppressor Gene ◽  
Resistant Cell ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Normal Tissues

Emerging evidence suggests that hypermethylation of HOXD10 plays an important role in human cancers. However, the biological and clinical impacts of HOXD10 overmethylation and its downstream targets in colorectal cancer remain unknown. We evaluated the methylation level of HOXD10 in paired cancer and normal tissues (n = 42) by using pyrosequencing, followed by validation of the methylation status of HOXD10 from The Cancer Genome Atlas (TCGA) datasets with 302 cancer tissues and 38 normal tissues. The biological function of HOXD10 was characterized in cell lines. We further evaluated the effects of HOXD10 and its targets on chemoresistance in our established resistant cell lines and clinical cohort (n = 66). HOXD10 was found frequently methylated in colorectal cancer, and its hypermethylation correlates with its low expression level, advanced disease, and lymph node metastasis. Functionally, HOXD10 acts as a tumor suppressor gene, in which HOXD10-expressing cells showed suppressed cell proliferation, colony formation ability, and migration and invasion capacity. Mechanistically, DNMT1, DNMT3B, and MeCP2 were recruited in the HOXD10 promoter, and demethylation by 5-Aza-2′-deoxycytidine (5-Aza-CdR) treatment or MeCP2 knockdown can sufficiently induce HOXD10 expression. HOXD10 regulates the expressions of miR-7 and IGFBP3 in a promoter-dependent manner. Restoration of the expression of HOXD10 in 5-fluorouracil (5-FU)-resistant cells significantly upregulates the expressions of miR-7 and IGFBP3 and enhances chemosensitivity to 5-FU. In conclusion, we provide novel evidence that HOXD10 is frequently methylated, silenced, and contributes to the development of colorectal cancers. Restoration of HOXD10 activates the expressions of miR-7 and IGFBP3 and results in an inhibited phenotype biologically, suggesting its potential therapeutic relevance in colorectal cancer (CRC).

scholarly journals Hypermethylation of heparanase 2 promotes colorectal cancer proliferation and is associated with poor prognosis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hui Zhang ◽  
Chenxin Xu ◽  
Chen Shi ◽  
Junying Zhang ◽  
Ting Qian ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Promoter Methylation ◽  
Genomic Analysis ◽  
Promoter Hypermethylation ◽  
Suppressor Gene ◽  
The Cancer Genome Atlas

Abstract Background The epigenetic abnormality of tumor-associated genes contributes to the pathogenesis of colorectal carcinoma (CRC). However, methylation in colorectal cancer is still poorly characterized. Method By integration of DNA methylation data from the GEO database and gene expression data from The Cancer Genome Atlas database, the aberrantly methylated genes involved in CRC tumorigenesis were identified. Subsequent in vitro experiments further validated their role in CRC. Results We performed integrative genomic analysis and identified HPSE2, a novel tumor suppressor gene that is frequently inactivated through promoter methylation in CRC. K-M survival analysis showed that hypermethylation–low expression of heparanase 2 (HPSE2) was related to poor patient prognosis. Overexpression of HPSE2 reduced cell proliferation in vivo and in vitro. HPSE2 could regulate the p53 signaling pathway to block the cell cycle in G1 phase. Conclusion HPSE2, a novel tumor suppressor gene that is frequently inactivated through promoter methylation in CRC. HPSE2 performs a tumor suppressive function by activating the p53/ p21 signaling cascade. The promoter hypermethylation of HPSE2 is a potential therapeutic target in patients with CRC, especially those with late-stage CRC.

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

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.

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.

scholarly journals Methylation status of CDH1 gene in samples of gastric mucous from brazilian patients with chronic gastritis infected by Helicobacter pylori

2010 ◽  
Vol 47 (1) ◽  
pp. 7-12 ◽  
Author(s):  
Erika Kague ◽  
Cristiane Melissa Thomazini ◽  
Maria Inês de Campo Moura Pardini ◽  
Fabrício de Carvalho ◽  
Celso Vieira Leite ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Tumor Suppressor ◽  
Chronic Gastritis ◽  
Direct Sequencing ◽  
Methylation Status ◽  
Cpg Islands ◽  
Pcr Primers ◽  
Suppressor Gene ◽  
Cdh1 Gene ◽  
H Pylori

CONTEXT: Gastric cancer is one of the top list of cancer types that most leads to death in Brazil and worldwide. Helicobacter pylori(H. pylori) is a class I carcinogen and infect almost 90% of chronic gastritis patients. Some genotypes confer different virulent potential to H. pylori and can increase the risk of gastritis development. Methylation of CpG islands can inactivate tumor suppressor genes and therefore, it can be involved in the tumorigenic process. CDH1 is a tumor suppressor gene that encodes the E-cadherin protein, which is important in maintaining cell-cell contacts. The inactivation of this gene can increase the chance of metastasis. Promoter methylation of CDH1 at early steps of gastric carcinogenesis is not yet completely understood. OBJECTIVE: In this study, we investigated the methylation status of CDH1 in chronic gastritis samples and correlated it with the presence of H. pylori. METHODS: Sixty gastric mucosal biopsies were used in this study. The detection of H. pylori was performed with the PCR primers specific to urease C gene. H. pylori genotyping was performed by PCR to cagA and vacA (s and m region). The methylation status of these gene CDH1 was analyzed using methylation-specific polymerase chain reaction and direct sequencing of the PCR products was performed using primers methylated and unmethylated in both forward and reverse directions. RESULTS: H. pylori was detected in 90% of chronic gastritis samples; among these 33% were cagA positive and 100% vacA s1. The genotype vacA s2/m1 was not detected in any sample analyzed. Methylation of CDH1 was detected in 63.3% of chronic gastritis samples and 95% of them were also H. pylori-positive. CONCLUSION: This work suggests that CDH1 gene methylation and H. pylori infection are frequent events in samples from Brazilian patients with chronic gastritis and reinforces the correlation between H. pylori infection and CDH1 inactivation in early steps of gastric tumorigenesis.

scholarly journals Promoter Methylation Precedes Chromosomal Alterations in Colorectal Cancer Development

2006 ◽  
Vol 28 (5-6) ◽  
pp. 247-257 ◽  
Author(s):  
Sarah Derks ◽  
Cindy Postma ◽  
Peter T. M. Moerkerk ◽  
Sandra M. van den Bosch ◽  
Beatriz Carvalho ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Promoter Methylation ◽  
Chromosomal Abnormalities ◽  
Methylation Status ◽  
Colorectal Carcinogenesis ◽  
Cancer Development ◽  
Comparative Genomic ◽  
Early Event ◽  
Chromosomal Alterations ◽  
Normal Tissues

Background: Colorectal cancers are characterized by genetic and epigenetic alterations. This study aimed to explore the timing of promoter methylation and relationship with mutations and chromosomal alterations in colorectal carcinogenesis. Methods: In a series of 47 nonprogressed adenomas, 41 progressed adenomas (malignant polyps), 38 colorectal carcinomas and 18 paired normal tissues, we evaluated promoter methylation status of hMLH1, O6MGMT, APC, p14ARF, p16INK4A, RASSF1A, GATA-4, GATA-5, and CHFR using methylation-specific PCR. Mutation status of TP53, APC and KRAS were studied by p53 immunohistochemistry and sequencing of the APC and KRAS mutation cluster regions. Chromosomal alterations were evaluated by comparative genomic hybridization. Results: Our data demonstrate that nonprogressed adenomas, progressed adenomas and carcinomas show similar frequencies of promoter methylation for the majority of the genes. Normal tissues showed significantly lower frequencies of promoter methylation of APC, p16INK4A, GATA-4, and GATA-5 (P-values: 0.02, 0.02, 1.1×10−5 and 0.008 respectively). P53 immunopositivity and chromosomal abnormalities occur predominantly in carcinomas (P values: 1.1×10−5 and 4.1×10−10). Conclusions: Since promoter methylation was already present in nonprogressed adenomas without chromosomal alterations, we conclude that promoter methylation can be regarded as an early event preceding TP53 mutation and chromosomal abnormalities in colorectal cancer development.

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.

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