Roles of Methylated DNA Biomarkers in Patients with Colorectal Cancer

Ma, Zhiyao; Williams, Marissa; Cheng, Yuen Yee; Leung, Wai K.

doi:10.1155/2019/2673543

Cited by 36 publications

(34 citation statements)

References 47 publications

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“…Experimental evidence for the hypermethylation of the promoter region of LAMA1 in CRC patients is available [53]. NELL1 is a known tumor suppressor gene [54], whose hypermethylation is associated with poor survival outcomes [55]. Our results that NELL1 is a stage IV-specific hypermethylated gene resonates with the above findings.…”

Section: Stage-iv Salient Dmgssupporting

confidence: 82%

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

Raghavendran¹,

Muthamilselvan²,

Palaniappan³

2020

Preprint

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Background: Aberrant methylation of DNA acts epigenetically to skew the gene transcription rate up or down. In this study, we have developed a comprehensive computational framework for the stage-specific analysis of methylation patterns in colorectal cancer. Methods: Combining public-domain methylation and clinical data from TCGA, the methylation β-matrix was converted into M-value matrix, annotated with sample stages and analysed for stage-specific genes using multiple approaches involving stage-differentiated linear modelling of methylation patterns or their correlation with the phenotype and expression patterns. Differentially methylated genes (DMGs) were identified using a contrast against control samples (adjusted p-value <0.001 and |log fold-change of M-value| >2). These results were further filtered using a series of all possible pairwise stage contrasts (p-value <0.05) to obtain stage-specific DMGs. These were then subjected to a consensus analysis, followed by Kaplan-Meier survival analysis to explore the relationship between methylation and prognosis for the consensus stage-salient biomarkers. Results: We found significant genome-wide changes in methylation patterns in cancer samples relative to controls agnostic of stage. Our stage-differentiated analysis yielded the following stage-salient genes: one stage-I gene (FBN1), one stage II specific gene (FOXG1), one stage III specific gene (HCN1) and four stage IV specific genes (NELL1, ZNF135, FAM123A, LAMA1), which could be used for stage-specific diagnosis. All the biomarkers were hypermethylated, indicating down-regulation and signifying a CpG island Methylator Phenotype (CIMP) manifestation. A prognostic signature consisting of FBN1 and FOXG1was significantly associated with patient survival (p-value < 0.01) and could be used as a biomarker panel for early-stage CRC prognosis. Conclusion: Our workflow for stage-differentiated consensus analysis has yielded stage-salient diagnostic biomarkers as well as an early-stage prognostic biomarker panel. In addition, our studies have affirmed a novel CIMP-like signature in colorectal cancer, urging clinical validation.

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Section: Stage-iv Salient Dmgssupporting

confidence: 82%

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

Raghavendran¹,

Muthamilselvan²,

Palaniappan³

2020

Preprint

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“…The sensitivity and specificity of the diagnostic panel consisting of CEA, CA19-9, CA242, CA211, and CA724 were 83% and 95%, respectively, which were similar to those of detection of SEPT9 gene methylation in peripheral blood. The sensitivity and specificity of the most commonly used single serum CEA were lower than those of SEPT9 gene methylation[ 62 - 64 ]. Colonoscopy biopsy combined with pathological diagnosis is the golden standard for the diagnosis of CRC.…”

Section: Sept9 and Colorectal Cancermentioning

confidence: 99%

Structure and function of Septin 9 and its role in human malignant tumors

Sun¹,

Zheng²,

Li³

2020

WJGO

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The treatment and prognosis of malignant tumors are closely related to the time when the tumors are diagnosed; the earlier the diagnosis of the tumor, the better the prognosis. However, most tumors are not detected in the early stages of screening and diagnosis. It is of great clinical significance to study the correlation between multiple pathogeneses of tumors and explore simple, safe, specific, and sensitive molecular indicators for early screening, diagnosis, and prognosis. The Septin 9 ( SEPT9 ) gene has been found to be associated with a variety of human diseases, and it plays a role in the development of tumors. SEPT9 is a member of the conserved family of cytoskeletal GTPase, which consists of a P-loop-based GTP-binding domain flanked by a variable N-terminal region and a C-terminal region. SEPT9 is involved in many biological processes such as cytokinesis, polarization, vesicle trafficking, membrane reconstruction, deoxyribonucleic acid repair, cell migration, and apoptosis. Several studies have shown that SEPT9 may serve as a marker for early screening, diagnosis, and prognosis of some malignant tumors, and have the potential to become a new target for anti-cancer therapy. This article reviews the progress in research on the SEPT9 gene in early screening, diagnosis, and prognosis of tumors.

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“…To date, none of these markers have been used in clinical practice. Recently Draht et al [ 190 ] and Ma et al [ 191 ] comprehensively reviewed the published prognostic methylation markers for CRC and marked the most promising ones. Studies focusing on the hypermethylation of the IGFBP3 gene have shown correlations with a poor prognosis in CRC patients [ 175 , 192 , 193 ].…”

Section: Clinical Applications Of Dna Methylation Profilingmentioning

confidence: 99%

Methylation-Based Therapies for Colorectal Cancer

Červená

Siskova

Büchler

et al. 2020

Cells

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Colorectal carcinogenesis (CRC) is caused by the gradual long-term accumulation of both genetic and epigenetic changes. Recently, epigenetic alterations have been included in the classification of the CRC molecular subtype, and this points out their prognostic impact. As epigenetic modifications are reversible, they may represent relevant therapeutic targets. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), regulates gene expression. For many years, the deregulation of DNA methylation has been considered to play a substantial part in CRC etiology and evolution. Despite considerable advances in CRC treatment, patient therapy response persists as limited, and their profit from systemic therapies are often hampered by the introduction of chemoresistance. In addition, inter-individual changes in therapy response in CRC patients can arise from their specific (epi)genetic compositions. In this review article, we summarize the options of CRC treatment based on DNA methylation status for their predictive value. This review also includes the therapy outcomes based on the patient’s methylation status in CRC patients. In addition, the current challenge of research is to develop therapeutic inhibitors of DNMT. Based on the essential role of DNA methylation in CRC development, the application of DNMT inhibitors was recently proposed for the treatment of CRC patients, especially in patients with DNA hypermethylation.

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Roles of Methylated DNA Biomarkers in Patients with Colorectal Cancer

Cited by 36 publications

References 47 publications

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

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

Structure and function of Septin 9 and its role in human malignant tumors

Methylation-Based Therapies for Colorectal Cancer

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