Prognostic value of CpG island methylator phenotype among colorectal cancer patients: a systematic review and meta-analysis

Juo, Yen-Yi; Johnston, Fabian M.; Zhang, Dongyu; Juo, Hsin Hsuan; Wang, H.; Pappou, Emmanouil P.; Yu, Tosol; Easwaran, Hariharan; Baylin, Stephen B.; Engeland, Manon van; Ahuja, Nita

doi:10.1093/annonc/mdu149

Cited by 153 publications

(133 citation statements)

References 47 publications

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“…A meta-analysis that included 14 studies showed that MGMT methylation status was not associated with CRC prognosis [47], whereas RASSF1A promoter methylation has been associated with poor prognosis, although when assessed in plasma samples [30]. Furthermore, CIMP status also did not disclose prognostic value in our study, which is in accordance with a recent metaanalysis that found no significant effect of CIMP status in DFS or OS in 8 out of 11 and in 13 out of 19 studies previously published, respectively [48]. The same was reported regarding DSS, in 3 of 4 studies considering the classical CIMP panel [8].…”

Section: Discussionsupporting

confidence: 90%

A novel DNA methylation panel accurately detects colorectal cancer independently of molecular pathway

et al. 2018

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Background: Colorectal cancer (CRC) is one of the most incident cancers, associated with significant morbidity and mortality, and usually classified into three main molecular pathways: chromosomal instability, microsatellite instability (MSI) and CpG island methylator phenotype (CIMP). Currently, available screening methods are either costly or of limited specificity, impairing global implementation. More cost-effective strategies, including DNA methylation-based tests, might prove advantageous. Although some are already available, its performance is suboptimal, entailing the need for better candidate biomarkers. Herein, we tested whether combined use of APC, IGF2, MGMT, RASSF1A, and SEPT9 promoter methylation might accurately detect CRC irrespective of molecular subtype.Methods: Selected genes were validated using formalin-fixed paraffin-embedded tissues from 214 CRC and 50 non-malignant colorectal mucosae (CRN). Promoter methylation levels were assessed using real-time quantitative methylation-specific PCR. MSI and CIMP status were determined. Molecular data were correlated with standard clinicopathological features. Diagnostic and prognostic performances were evaluated by receiver operator characteristics curve and survival analyses, respectively.Results: Except for IGF2, promoter methylation levels were significantly higher in CRC compared to CRN. A threegene panel (MGMT, RASSF1A, SEPT9) identified malignancy with 96.6% sensitivity, 74.0% specificity and 91.5 positive predictive value (area under the curve: 0.97), independently of tumor location, stage, and molecular pathway. Conclusions:Combined promoter methylation analysis of MGMT/RASSF1A/SEPT9 displays a better performance than currently available epigenetic-based biomarkers for CRC, providing the basis for the development of a non-invasive assay to detect CRC irrespective of the molecular pathway.

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Section: Discussionsupporting

confidence: 90%

A novel DNA methylation panel accurately detects colorectal cancer independently of molecular pathway

et al. 2018

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“…Barault et al reported that the 5-year survival rate of the patients with a MSI stable genotype and positive for CIMP was poor. Juo et al found that CIMP is an independent risk factor for poor prognosis in colorectal cancer [59]. This finding indicates that low expression of the genes in right-sided colon cancer is possibly related to hypermethylation.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 97%

Distinguishable Prognostic Signatures of Left- and Right-Sided Colon Cancer: a Study Based on Sequencing Data

Liang

Zeng

Qin

et al. 2018

Cell Physiol Biochem

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Key WordsLeft-and right-sided • Colon cancer • Prognosis • TCGA Abstract Background/Aims: Left-and right-sided colon cancers are considered to be two different diseases and have altered outcomes. However, specific molecules to predict the prognosis of left-and right-sided colon cancers are currently lacking. Methods: Expression profiling of colon cancer were downloaded from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) of left-and right-sided colon cancers were compared by DESeq analysis. The prognostic values of DEGs were assessed by univariate and multivariate Cox regression. Prognostic index models of two side colon cancers were conducted with prognostic values genes, respectively. Interaction of DEGs was then analyzed by the protein-protein interaction (PPI). Different biology function of two sides of colon cancer was assessed by Gene Set Enrichment Analysis (GSEA). Results: A total of 167 DEGs were identified between left-and right-sided colon cancers based on TCGA data. Using univariate COX regression analysis, five genes (PHACTR3, CKMT2, CYP2W1, ERFE, HOXC4) were related to overall survival in left-sided, and eight distinguishable genes (EREG, ERFE, HOXC6, SLC22A31, TFF1, GFI1, ZG16, RASL10B) in right-sided. Further, left-sided prognostic model was established with PHACTR3 and CKMT2 (HR=2.040; 95%CI=1.004-4.145; P=0.049). Distinguishable prognostic signature for right-sided colon cancer was established based on EREG, ERFE, GFI1, and RASL10B (HR=3.530; 95%CI: 1.934-6.444; P<0.001) in multivariate analysis. PPI analysis of 167 DEGs showed that CCL5, GNG4, GNLY, GZMH, DRD2, and FASLG genes were at the core of interaction network. In GSEA function analysis, four pathways, including antigen processing and presentation, natural killer cell mediated cytotoxicity, intestinal immune network for Iga production, and type I diabetes mellitus, were significantly enriched in the DEGs of the right-sided colon cancer. Conclusions: This study constructs a panel of potential prognostic model of left-and right-sided colon cancers, respectively. We also provide molecular biological alterations between left-and rightsided colon cancers.

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“…This pathway is characterized by BRAF V600E mutation and hypermethylation in CpG-rich gene promoters, thereby leading to transcriptional inactivation of a large number of genes, including the MMR gene MLH1. The silencing of this gene is responsible for the development of MSI [29,56,57].…”

Section: Microsatellite Instability In Sporadic Colorectal Cancermentioning

confidence: 99%

“…Very recently, Juo et al [57] analyzed thirty-three studies reporting survival in 10,635 patients to determine the prognostic significance of CIMP status in CRC. Nineteen studies provide data suitable for meta-analysis.…”

Section: Microsatellite Instability In Sporadic Colorectal Cancermentioning

confidence: 99%

Microsatellite instability in colorectal cancer: clinicopathological significance

Setaffy¹,

Langner²

2015

pjp

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Although often viewed as a single disease, colorectal cancer more accurately represents a constellation of heterogeneous subtypes that result from different combinations of genetic events and epigenetic alterations. Chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) have been identified as the three major molecular characteristics, which interact with other significant mutations, such as mutations in the KRAS and BRAF genes. High-level MSI (MSI-H) is of eminent clinical importance. It is the seminal molecular feature for the identification of individuals with Lynch syndrome, but it may also occur in sporadic cancers with CIMP phenotype, which arise from serrated precursor lesions. MSI-H status is a marker of favorable prognosis and may be used for outcome prediction, that is, molecular grading. Among others, mucinous and medullary histology, signet-ring cell differentiation, and a marked anti-tumoral immune response are histological features suggesting MSI. Universal tumor testing is recommended and may be performed using immunohistochemistry (mismatch repair protein expression) or molecular analysis, as has recently been recommended by an international task force. In this review, we consider in detail the molecular pathogenesis of colorectal cancer, focusing on the diagnosis of MSI in both hereditary and sporadic tumors.

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Prognostic value of CpG island methylator phenotype among colorectal cancer patients: a systematic review and meta-analysis

Cited by 153 publications

References 47 publications

A novel DNA methylation panel accurately detects colorectal cancer independently of molecular pathway

A novel DNA methylation panel accurately detects colorectal cancer independently of molecular pathway

Distinguishable Prognostic Signatures of Left- and Right-Sided Colon Cancer: a Study Based on Sequencing Data

Microsatellite instability in colorectal cancer: clinicopathological significance

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