Hypermethylated DNA as a biomarker for colorectal cancer: a systematic review

Rasmussen, Simon Ladefoged; Krarup, Henrik; Gotschalck, Kåre Andersson; Pedersen, Inge Søkilde; Madsen, Poul Thøis; Thorlacius-Ussing, Ole

doi:10.1111/codi.13336

Cited by 72 publications

(52 citation statements)

References 94 publications

(178 reference statements)

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“…The gene promoter regions were initially selected based on a systematic literature search [10]. We used this approach to evaluate proven CRC hypermethylation biomarkers, previously analysed in tumour remote media like blood and stool samples.…”

Section: Discussionmentioning

confidence: 99%

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Hypermethylated DNA, a circulating biomarker for colorectal cancer detection

et al. 2017

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BackgroundColorectal cancer (CRC) is one of the most common cancers in the western world. Screening is an efficient method of reducing cancer-related mortality. Molecular biomarkers for cancer in general and CRC in particular have been proposed, and hypermethylated DNA from stool or blood samples are already implemented as biomarkers for CRC screening.We aimed to evaluate the performance of proven hypermethylated DNA promoter regions as plasma based biomarkers for CRC detection.MethodsWe conducted a cross-sectional case-control study of 193 CRC patients and 102 colonoscopy-verified healthy controls. Using methylation specific polymerase chain reaction, we evaluated 30 DNA promoter regions previously found to be CRC specific. We used multivariable logistic regression with stepwise backwards selection, and subsequent leave-pair-out cross validation, to calculate the optimism corrected area under the receiver operating characteristics curve (AUC) for all stage as well as early stage CRC.ResultsNone of the individual DNA promoter regions provided an overall sensitivity above 30% at a reasonable specificity. However, seven hypermethylated promoter regions (ALX4, BMP3, NPTX2, RARB, SDC2, SEPT9, and VIM) along with the covariates sex and age yielded an optimism corrected AUC of 0.86 for all stage CRC and 0.85 for early stage CRC. Overall sensitivity for CRC detection was 90.7% at 72.5% specificity using a cut point value of 0.5.ConclusionsIndividual hypermethylated DNA promoter regions have limited value as CRC screening markers. However, a panel of seven hypermethylated promoter regions show great promise as a model for CRC detection.

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Section: Discussionmentioning

confidence: 99%

“…We aimed to establish a multivariable prediction model for CRC detection using a panel of 30 promoter regions, previously evaluated in stool or blood, as biomarkers for CRC with varying sensitivities [10]. Thus, we defined the outcome variable as patients with/without CRC.…”

Section: Methodsmentioning

confidence: 99%

Hypermethylated DNA, a circulating biomarker for colorectal cancer detection

et al. 2017

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“…PHACTR3 is a new hypermethylated gene in CRC exhibiting good performance in stool DNA testing and has complementary value to the fecal immunochemical test in colorectal cancer [26]. Hypermethylation of the PHACTR3 promoter measured in stool samples could be used as a colorectal cancer biomarker and provide prognostic information [27]. CKMT2 was not studied in colon cancer.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

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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“…The CpG sites in LINE-1 are usually heavily methylated and genome-wide loss of methylation from these sites has been regarded as a common epigenetic event in malignancy [19]. The p16 tumor suppressor gene is found altered in a wide range of human cancers like endometrial carcinoma, hepatic, gastric, and colorectal cancer [20–22], and it has been suggested as a biomarker for colorectal cancer [23]. It encodes a specific inhibitor of cyclin-dependent kinase 4 and 6 and plays a pivotal role in tumor suppressor networks through inducing cellular senescence that acts as a barrier to cellular transformation by oncogenic signals [24].…”

Section: Introductionmentioning

confidence: 99%

High levels of circulating folate concentrations are associated with DNA methylation of tumor suppressor and repair genes p16, MLH1, and MGMT in elderly Chileans

et al. 2017

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BackgroundChanges in DNA methylation, one of the most studied epigenetic mechanisms, are considered an initial marker for early cancer detection. We evaluated how availability of dietary factors (folates and vitamin B12) involved in one-carbon metabolism may contribute to DNA methylation changes of cancer-related genes in human subjects.MethodsWe studied, by pyrosequencing, the methylation of tumor suppressor gene p16, DNA repair genes MLH1 and MGMT, and the repetitive element LINE-1 (as a surrogate for global DNA methylation), in blood of elderly individuals (n = 249) who had been exposed to folic acid (FA) through FA-fortified wheat flour during the last 12 years.ResultsWe found that serum folate and to a lesser extent, vitamin B12 concentrations, were significantly correlated with DNA methylation of p16, MLH1, and MGMT, but not with LINE-1. High serum folate concentrations (>45.3 nmol/L) were present in 31.1% of the participants. Although the methylated fraction of CpG sites in p16, MLH1, and MGMT was low (1.17–3.8%), high folate concentrations were significantly associated with methylation at the 3rd tertile of specific CpG sites in all genes with OR between 1.97 and 4.17.ConclusionsThis study shows that a public policy, like food fortification with FA that increases circulating serum folate levels, could affect methylation levels of specific genes linked to cancer risk. Our present results deserve additional studies to clarify the real impact of high FA levels for risk of cancer in a whole population chronically exposed to a fortified food such as wheat flour.Trial registration ISRCTN 48153354 and ISRCTN 02694183

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Hypermethylated DNA as a biomarker for colorectal cancer: a systematic review

Cited by 72 publications

References 94 publications

Hypermethylated DNA, a circulating biomarker for colorectal cancer detection

Hypermethylated DNA, a circulating biomarker for colorectal cancer detection

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

High levels of circulating folate concentrations are associated with DNA methylation of tumor suppressor and repair genes p16, MLH1, and MGMT in elderly Chileans

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