Progressive alteration of DNA methylation of Alu, MGMT, MINT2, and TFPI2 genes in colonic mucosa during colorectal cancer development

2021 ◽  
pp. 1-6
Author(s):  
Ben Kang ◽  
Hyun Seok Lee ◽  
Seong Woo Jeon ◽  
Soo Yeun Park ◽  
Gyu Seog Choi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Healthy Subjects ◽  
Large Scale ◽  
Methylation Status ◽  
Clinical Information ◽  
Field Cancerization ◽  
Aberrant Methylation ◽  
Clinical Value ◽  
Mortality And Morbidity

BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is characterized by different pathways of carcinogenesis and is a heterogeneous disease with diverse molecular landscapes that reflect histopathological and clinical information. Changes in the DNA methylation status of colon epithelial cells have been identified as critical components in CRC development and appear to be emerging biomarkers for the early detection and prognosis of CRC. OBJECTIVE: To explore the underlying disease mechanisms and identify more effective biomarkers of CRC. METHODS: We compared the levels and frequencies of DNA methylation in 11 genes (Alu, APC, DAPK, MGMT, MLH1, MINT1, MINT2, MINT3, p16, RGS6, and TFPI2) in colorectal cancer and its precursor adenomatous polyp with normal tissue of healthy subjects using pyrosequencing and then evaluated the clinical value of these genes. RESULTS: Aberrant methylation of Alu, MGMT, MINT2, and TFPI2 genes was progressively accumulated during the normal-adenoma-carcinoma progression. Additionally, CGI methylation occurred either as an adenoma-associated event for APC, MLH1, MINT1, MINT31, p16, and RGS6 or a tumor-associated event for DAPK. Moreover, relatively high levels and frequencies of DAPK, MGMT, and TFPI2 methylation were detected in the peritumoral nonmalignant mucosa of cancer patients in a field-cancerization manner, as compared to normal mucosa from healthy subjects. CONCLUSION: This study identified several biomarkers associated with the initiation and progression of CRC. As novel findings, they may have important clinical implications for CRC diagnostic and prognostic applications. Further large-scale studies are needed to confirm these findings.

scholarly journals Multiple gene promoter methylation and clinical stage in adjacent normal tissues: Effect on prognosis of colorectal cancer in Taiwan

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Chih-Hsiung Hsu ◽  
Cheng-Wen Hsiao ◽  
Chien-An Sun ◽  
Wen-Chih Wu ◽  
Tsan Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Tumor Tissue ◽  
Clinical Stage ◽  
Methylation Status ◽  
Aberrant Methylation ◽  
Event Free Survival ◽  
Free Survival ◽  
Normal Tissues ◽  
Colorectal Cancer Patients

AbstractThis study provide an insight that the panel genes methylation status in different clinical stage tended to reflect a different prognosis even in matched normal tissues, to clinical recommendation. We enrolled 153 colorectal cancer patients from a medical center in Taiwan and used the candidate gene approach to select five genes involved in carcinogenesis pathways. We analyzed the relationship between DNA methylation with different cancer stages and the prognostic outcome. There were significant trends of increasing risk of 5-year time to progression and event-free survival of subjects with raising number of hypermethylation genes both in normal tissue and tumor tissue. The group with two or more genes with aberrant methylation in the advanced cancer stages (Me/advanced) had lower 5-year event-free survival among patients with colorectal cancer in either normal or tumor tissue. The adjusted hazard ratios in the group with two or more genes with aberrant methylation with advanced cancer stages (Me/advanced) were 8.04 (95% CI, 2.80–23.1; P for trend <0.01) and 8.01 (95% CI, 1.92–33.4; P for trend <0.01) in normal and tumor tissue, respectively. DNA methylation status was significantly associated with poor prognosis outcome. This finding in the matched normal tissues of colorectal cancer patients could be an alternative source of prognostic markers to assist clinical decision making.

scholarly journals Whole-blood DNA Methylation Markers for Risk Stratification in Colorectal Cancer Screening: A Systematic Review

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 912 ◽  
Author(s):  
Raut ◽  
Guan ◽  
Schrotz-King ◽  
Brenner
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Risk Stratification ◽  
Colorectal Neoplasms ◽  
Whole Blood ◽  
Large Scale ◽  
Methylation Status ◽  
Population Characteristics ◽  
Risk Scores ◽  
Study Population

DNA methylation profiles within whole-blood samples have been reported to be associated with colorectal cancer (CRC) occurrence and might enable risk stratification for CRC. We systematically reviewed and summarized studies addressing the association of whole-blood DNA methylation markers and risk of developing CRC or its precursors. We searched PubMed and ISI Web of Knowledge to identify relevant studies published until 12th November 2018. Two reviewers independently extracted data on study population characteristics, candidate genes, methylation measurement methods, methylation levels of patients in comparison to healthy controls, p-values, and odds ratios of the markers. Overall, 19 studies reporting 102 methylation markers for risk assessment of colorectal neoplasms met our inclusion criteria. The studies mostly used Methylation Specific Polymerase Chain Reaction (MS-PCR) for assessing the methylation status of a defined set of genes. Only two studies applied array-based genome-wide assays to assess the methylation levels. Five studies incorporated panels consisting of 2–10 individual methylation markers to assess their potential for stratifying the risk of developing colorectal neoplasms. However, none of these associations was confirmed in an independent cohort. In conclusion, whole-blood DNA methylation markers may be useful as biomarkers for risk stratification in CRC screening, but reproducible risk prediction algorithms are yet to be established by large scale epigenome-wide studies with thorough validation of results in prospective study cohorts including large screening populations. The possibilities of enhancing predictive power by combining methylation data with polygenetic risk scores and environmental risk factors need to be explored.

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 Multiplexed DNA Methylation Analysis in Colorectal Cancer Using Liquid Biopsy and Its Diagnostic and Predictive Value

2021 ◽  
Vol 43 (3) ◽  
pp. 1419-1435
Author(s):  
Walter Pulverer ◽  
Kristi Kruusmaa ◽  
Silvia Schönthaler ◽  
Jasmin Huber ◽  
Marko Bitenc ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Therapy Monitoring ◽  
Methylation Status ◽  
Methylation Analysis ◽  
Microarray Experiments ◽  
Specific Pcr ◽  
Colonic Adenomas ◽  
Methylation Sensitive Restriction Enzyme ◽  
Dna Methylation Analysis

Early diagnosis of colorectal cancer (CRC) is of high importance as prognosis depends on tumour stage at the time of diagnosis. Detection of tumour-specific DNA methylation marks in cfDNA has several advantages over other approaches and has great potential for solving diagnostic needs. We report here the identification of DNA methylation biomarkers for CRC and give insights in our methylation-sensitive restriction enzyme coupled qPCR (MSRE-qPCR) system. Targeted microarrays were used to investigate the DNA methylation status of 360 cancer-associated genes. Validation was done by qPCR-based approaches. A focus was on investigating marker performance in cfDNA from 88 patients (44 CRC, 44 controls). Finally, the workflow was scaled-up to perform 180plex analysis on 110 cfDNA samples, to identify a DNA methylation signature for advanced colonic adenomas (AA). A DNA methylation signature (n = 44) was deduced from microarray experiments and confirmed by quantitative methylation-specific PCR (qMSP) and by MSRE-qPCR, providing for six genes’ single areas under the curve (AUC) values of >0.85 (WT1, PENK, SPARC, GDNF, TMEFF2, DCC). A subset of the signatures can be used for patient stratification and therapy monitoring for progressed CRC with liver metastasis using cfDNA. Furthermore, we identified a 35-plex classifier for the identification of AAs with an AUC of 0.80.

scholarly journals Predictors of Biological Age: The Implications for Wellness and Aging Research

2021 ◽  
Vol 7 ◽  
pp. 233372142110464
Author(s):  
Trevor Lohman ◽  
Gurinder Bains ◽  
Lee Berk ◽  
Everett Lohman
Keyword(s):  
Dna Methylation ◽  
Lifestyle Modification ◽  
Biological Age ◽  
Current Evidence ◽  
Biological Aging ◽  
Clinical Value ◽  
Aging Research ◽  
Mortality And Morbidity ◽  
Morbidity Risk ◽  
Pharmaceutical Interventions

As healthspan and lifespan research breakthroughs have become more commonplace, the need for valid, practical markers of biological age is becoming increasingly paramount. The accessibility and affordability of biological age predictors that can reveal information about mortality and morbidity risk, as well as remaining years of life, has profound clinical and research implications. In this review, we examine 5 groups of aging biomarkers capable of providing accurate biological age estimations. The unique capabilities of these biomarkers have far reaching implications for the testing of both pharmaceutical and non-pharmaceutical interventions designed to slow or reverse biological aging. Additionally, the enhanced validity and availability of these tools may have increasingly relevant clinical value. The authors of this review explore those implications, with an emphasis on lifestyle modification research, and provide an overview of the current evidence regarding 5 biological age predictor categories: Telomere length, composite biomarkers, DNA methylation “epigenetic clocks,” transcriptional predictors of biological age, and functional age predictors.

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 DNA Methylation in Colorectal cancer—Impact on Screening and Therapy Monitoring Modalities?

2007 ◽  
Vol 23 (1-2) ◽  
pp. 51-71 ◽  
Author(s):  
Marion Zitt ◽  
Matthias Zitt ◽  
Hannes M. Müller
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Early Detection ◽  
Therapy Monitoring ◽  
Specific Treatment ◽  
Genetic Alterations ◽  
Neoplastic Disease ◽  
Aberrant Methylation ◽  
Colon Polyps ◽  
Histological Progression

Colorectal cancer (CRC) is a common malignancy. It arises from benign neoplasms and evolves into adenocarcinomas through a stepwise histological progression sequence, proceeding from either adenomas or hyperplastic polyps/serrated adenomas. Genetic alterations have been associated with specific steps in this adenoma-carcinoma sequence and are believed to drive the histological progression of CRC. Recently, epigenetic alterations (especially DNA methylation) have been shown to occur in colon polyps and CRC. The aberrant methylation of genes appears to act together with genetic alterations to drive the initiation and progression of colon polyps to CRC.DNA methylation changes have been recognized as one of the most common molecular alterations in human tumors, including CRC. Because of the ubiquity of DNA methylation changes and the ability to detect methylated DNA in several body fluids (blood, stool), this specifically altered DNA may serve, on the one hand, as a possible new screening marker for CRC and, on the other hand, as a tool for therapy monitoring in patients having had neoplastic disease of the colorectum.As many CRC patients present with advanced disease, early detection seems to be one of the most important approaches to reduce mortality. Therefore, an effective screening test would have substantial clinical benefits. Furthermore, early detection of progression of disease in patients having had CRC permits immediate commencement of specific treatment regimens (e.g. curative resection of liver and lung metastases) and probably longer survival and better quality of life.

scholarly journals Hypermethylation-Associated Silencing of miR-125a and miR-125b: A Potential Marker in Colorectal Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Hui Chen ◽  
Zhiying Xu
Keyword(s):  
Colorectal Cancer ◽  
Cpg Island ◽  
Methylation Status ◽  
Pcr Analysis ◽  
Aberrant Methylation ◽  
Dna Hypermethylation ◽  
Expression Levels ◽  
Qrt Pcr ◽  
Potential Marker ◽  
Potential Biomarker

Background. MicroRNAs (miRNAs) have been found to be downregulated in human colorectal cancer (CRC), and some of them may function as tumor suppressor genes (TSGs). Aberrant methylation triggers the inactivation of TSGs during tumorigenesis.Patients and Methods. We investigated the methylation status of miR-125 family in CRC tissues and adjacent nontumor tissues by using bisulfite sequencing PCR (BSP). The expression levels of the two miRNAs were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR).Results. The methylation frequency of miR-125a and miR-125b was higher in CRC tissues. QRT-PCR analysis showed that miR-125a and miR-125b were significantly downregulated in CRC tissues. Moreover, the expression levels of miR-125a and miR-125b were inversely correlated to CpG island methylation in CRC.Conclusions. Our results suggest that DNA hypermethylation may be involved in the inactivation of miR-125a and miR-125b in CRC, and hypermethylation of miR-125 is a potential biomarker for clinical outcome.

scholarly journals THE ROLE OF ABERRANT METHYLATED IN GENES APC, RASSF1A AND ITGA4 FOR DIAGNOSIS OF COLORECTAL CANCER

2017 ◽  
Vol 8 (4) ◽  
pp. 8-14
Author(s):  
O I Brovkina ◽  
M G Gordiev ◽  
A N Toropovskiy ◽  
D S Khodyrev ◽  
Au Vyacheslavovich Nikitin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Diagnostic Test ◽  
Large Scale ◽  
High Reliability ◽  
Rectal Adenocarcinoma ◽  
Test System ◽  
Aberrant Methylation ◽  
Tissue Samples ◽  
Ras Family ◽  
The Republic

The “gold standard” of diagnosis of colorectal cancer (CRC) is a colonoscopy. Despite the high reliability, this method is not applicable in large-scale population screening or in estimation of the disease dynamics in a particular patient. In this study, we conducted an investigation of aberrant methylation in the APC, RASSF1A and ITGA4 genes. The study included 150 pairs of tumor tissue samples with known mutation status of the RAS family genes and the surrounding histologically unchanged tissue of patients with rectal adenocarcinoma treated at the Republican Clinical Oncology Dispensary of the Ministry of Health of the Republic of Tatarstan. The methylation profiles were studied using MethyLight PCR. The most difference in the methylation between tumor and healthy tissue was observed for the ITGA4 gene (sensitivity 78%, specificity 92.7%). For the APC gene sensitivity was 32%, specificity -93.3%, for the RASSF1 gene sensitivity was 85.3%, specificity - 56.7%. Previous data on the aberrant methylation of the SEPT9 and VIM genes and new data on the APC, RASSF1A and ITGA4 genes were compared with the mutations status in the KRAS and NRAS genes. The DNA of tumor samples was significantly more often methylated in the SEPT9 (P= 0.0018) and ITGA4 (P = 0.0044) genes in the group of patients carrying mutations in the KRAS or NRAS genes, in contrast to the DNA of tumor samples of non-carriers. In statistical analysis of the effectiveness of the diagnostic test system, it was shown that our model, which includes five methylation markers (APC, RASSF1A, ITGA4, SEPT9 and VIM), has the best sensitivity and specificity (82.7% and 97.3%, respectively). The obtained model of the diagnostic test system is proposed to be used for diagnostic problems.

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