DNA‑methylated gene markers for colorectal cancer in TCGA database

Zhang, Hui; Sun, Xun; Lu, Ya; Wu, Jianzhong; Feng, Jifeng

doi:10.3892/etm.2020.8565

Cited by 12 publications

(12 citation statements)

References 33 publications

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“…ZNF proteins, such as ZNF346, ZNF638, and ZNF768, are used as capture antigens in CRC to detect autoantibodies [ 38 ]. Furthermore, in a previous study, epigenetically activated ZNF726 was identified as a prognosis‑associated gene for CRC [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Aberrantly methylated-differentially genes and pathways among Iranian patients with colorectal cancer

2021

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Background Methylation plays an important role in colorectal cancer (CRC) pathogenesis. The goal of this study was to identify aberrantly differentially methylated genes (DMGs) and pathways through bioinformatics analysis among Iranian CRC patients using Methylation Next Generation Sequencing. Methods This study has integrated results of SureSelectXT Methyl-Seq Target with the potential key candidate genes and pathways in CRC. Six CRC and six samples of normal colon were integrated and deeply analyzed. In addition to this gene methylation profiling, several other gene methylation profiling datasets were obtained from Gene Expression Omnibus (GEO) and TCGA datasets. DMGs were sorted and candidate genes and enrichment pathways were analyzed. DMGs-associated protein–protein interaction network (PPI) was constructed based on the STRING online database. Results Totally, 320 genes were detected as common genes between our patients and selected GEO and TCGA datasets from the Agilent SureSelect analysis with selecting criteria of p-value < 0.05 and FC ≥ 1.5. DMGs were identified from hyper-DMGs PPI network complex and 10 KEGG pathways were identified. The most important modules were extracted from MCODE, as most of the corresponding genes were involved in cellular process and protein binding. Conclusions Hub genes including WNT2, SFRP2, ZNF726 and BMP2 were suggested as potentially diagnostic and therapeutic targets for CRC.

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Section: Discussionmentioning

confidence: 99%

Aberrantly methylated-differentially genes and pathways among Iranian patients with colorectal cancer

2021

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“…Epigenetic modification refers to the heritable changes that do not directly affect the DNA sequence per se , but rather its accessibility and chromatin structure, attributed to incidences of DNA methylation and histone modifications that lead to the dysregulation of gene expression [ 171 ]. In colon cancer, dysregulation that elicits genomic instability causing tumor initiation can derive from gene promoter CpG island methylation as observed in tumor-suppressors Krüeppel-like factor 6 (KLF6), KLF4, and zinc finger protein 726 (ZNF726) silencing; through direct hypermethylation of one allele demonstrated in human mutL homolog 1 (hMLH1) and cyclin-dependent kinase inhibitor 2A (CDKN2A); and through DNA hypomethylation such as in the case of LINC00460 that promotes metastasis [ 172 , 173 , 174 , 175 ].…”

Section: Classical Mechanisms Of Resistancementioning

confidence: 99%

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

Azwar

Seow

Abdullah

et al. 2021

Biology

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5-Fluorouracil (5-FU) plus leucovorin (LV) remain as the mainstay standard adjuvant chemotherapy treatment for early stage colon cancer, and the preferred first-line option for metastatic colon cancer patients in combination with oxaliplatin in FOLFOX, or irinotecan in FOLFIRI regimens. Despite treatment success to a certain extent, the incidence of chemotherapy failure attributed to chemotherapy resistance is still reported in many patients. This resistance, which can be defined by tumor tolerance against chemotherapy, either intrinsic or acquired, is primarily driven by the dysregulation of various components in distinct pathways. In recent years, it has been established that the incidence of 5-FU resistance, akin to multidrug resistance, can be attributed to the alterations in drug transport, evasion of apoptosis, changes in the cell cycle and DNA-damage repair machinery, regulation of autophagy, epithelial-to-mesenchymal transition, cancer stem cell involvement, tumor microenvironment interactions, miRNA dysregulations, epigenetic alterations, as well as redox imbalances. Certain resistance mechanisms that are 5-FU-specific have also been ascertained to include the upregulation of thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase, and the downregulation of thymidine phosphorylase. Indeed, the successful modulation of these mechanisms have been the game plan of numerous studies that had employed small molecule inhibitors, plant-based small molecules, and non-coding RNA regulators to effectively reverse 5-FU resistance in colon cancer cells. It is hoped that these studies would provide fundamental knowledge to further our understanding prior developing novel drugs in the near future that would synergistically work with 5-FU to potentiate its antitumor effects and improve the patient’s overall survival.

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“…Here we have found that epigenetic silencing of ZNF135 is a key feature of stage-IV CRC. It is interesting that another member of the zinc-nger protein family, ZNF726, has been recently identi ed as the only methylated gene signi cantly associated with OS in patients with CRC, without regard for pathologic stage [63]. FAM123A, also known as AMER2, is associated with microtubule proteins [64], and is a paralog of the well-documented FAM123B, a tumor-suppressor whose loss-of-function by mutation, methylation and copy-number aberrations is known to play a pivotal role in colorectal cancer, especially in older patients [65,66,67].…”

Section: Discussionmentioning

confidence: 99%

Stage-differentiated modelling of DNA methylation landscapes uncovers salient biomarkers and prognostic signatures in colorectal cancer progression

Muthamilselvan

Raghavendran

Palaniappan

2021

Preprint

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Background: Aberrant DNA methylation acts epigenetically to skew the gene transcription rate up or down, with causative roles in the etiology of cancers. However research on the role of DNA methylation in driving the progression of cancers is limited. In this study, we have developed a comprehensive computational framework for the stage-differentiated modelling of DNA methylation landscapes in colorectal cancer (CRC), and unravelled significant stagewise signposts of CRC progression. Methods: The methylation β - matrix was derived from the public-domain TCGA data, converted into M-value matrix, annotated with AJCC stages, and analysed for stage-salient genes using multiple approaches involving stage-differentiated linear modelling of methylation patterns and/or expression patterns. Differentially methylated genes (DMGs) were identified using a contrast against controls (adjusted p-value <0.001 and |log fold-change of M-value| >2). These results were filtered using a series of all possible pairwise stage contrasts (p-value <0.05) to obtain stage-salient DMGs. These were then subjected to a consensus analysis, followed by Kaplan–Meier survival analysis to evaluate the impact of methylation patterns of consensus stage-salient biomarkers on disease prognosis.Results: We found significant genome-wide changes in methylation patterns in cancer cases relative to controls agnostic of stage. Our stage-differentiated analysis yielded the following stage-salient genes: one stage-I gene (FBN1), one stage-II gene (FOXG1), one stage-III gene (HCN1) and four stage-IV genes (NELL1, ZNF135, FAM123A, LAMA1). All the biomarkers were hypermethylated, indicating down-regulation and signifying a CpG island Methylator Phenotype (CIMP) manifestation. A significant prognostic signature consisting of FBN1 and FOXG1 survived all the steps of our analysis pipeline, and represents a novel early-stage biomarker. Conclusions: We have designed a workflow for stage-differentiated consensus analysis, and identified stage-salient diagnostic biomarkers and an early-stage prognostic biomarker panel. Our studies further yield a novel CIMP-like signature of potential clinical import underlying CRC progression.

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DNA‑methylated gene markers for colorectal cancer in TCGA database

Cited by 12 publications

References 33 publications

Aberrantly methylated-differentially genes and pathways among Iranian patients with colorectal cancer

Aberrantly methylated-differentially genes and pathways among Iranian patients with colorectal cancer

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

Stage-differentiated modelling of DNA methylation landscapes uncovers salient biomarkers and prognostic signatures in colorectal cancer progression

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