Leukocyte DNA methylation and colorectal cancer among male smokers

Gao, Ying; Killian, Keith; Zhang, Hong; Yu, Kai; Li, Qi-Zhai; Weinstein, Stephanie J.; Virtamo, Jarmo; Tucker, Margaret A.; Taylor, Philip R.; Albanês, Demetrius; Meltzer, Paul S.; Caporaso, Neil E.

doi:10.4251/wjgo.v4.i8.193

Cited by 11 publications

(18 citation statements)

References 51 publications

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“…Though many epigenetic studies rely on blood leukocytes as a surrogate for alterations in other diseased cell-types, 24–27,31–36 there is very little evidence supporting the validity of inferring epigenetic mechanisms of non-hematologic disorders from epigenetic analysis of blood leukocytes.…”

Section: Tissue and Cellular Heterogeneity: Challenges In Epigenetic mentioning

confidence: 99%

Molecular pathological epidemiology of epigenetics: emerging integrative science to analyze environment, host, and disease

et al. 2013

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Epigenetics acts as an interface between environmental / exogenous factors, cellular responses and pathological processes. Aberrant epigenetic signatures are a hallmark of complex multifactorial diseases, including non-neoplastic disorders (e.g., cardiovascular diseases, hypertension, diabetes mellitus, autoimmune diseases, and some infectious diseases) and neoplasms (e.g., leukemias, lymphomas, sarcomas, and breast, lung, prostate, liver and colorectal cancers). Epigenetic signatures (DNA methylation, mRNA and microRNA expression, etc.) may serve as biomarkers for risk stratification, early detection, and disease classification, as well as targets for therapy and chemoprevention. DNA methylation assays are widely applied to formalin-fixed paraffin-embedded archival tissue specimens as clinical pathology tests. To better understand the interplay between etiologic factors, cellular molecular characteristics, and disease evolution, the field of “Molecular Pathological Epidemiology (MPE)” has emerged as an interdisciplinary integration of “molecular pathology” and “epidemiology”, with a similar conceptual framework to systems biology and network medicine. In contrast to traditional epidemiologic research including genome-wide association studies (GWAS), MPE is founded on the unique disease principle; that is, each disease process results from unique profiles of exposomes, epigenomes, transcriptomes, proteomes, metabolomes, microbiomes, and interactomes in relation to the macro-environment and tissue microenvironment. The widespread application of epigenomics (e.g., methylome) analyses will enhance our understanding of disease heterogeneity, epigenotypes (CpG island methylator phenotype, LINE-1 hypomethylation, etc.), and host-disease interactions. MPE may represent a logical evolution of GWAS, termed “GWAS-MPE approach”. Though epigenome-wide association study attracts increasing attention, currently, it has a fundamental problem in that each cell within one individual has a unique, time-varying epigenome. This article will illustrate increasing contribution of modern pathology to broader public health sciences, which attests pivotal roles of pathologists in the new integrated MPE science towards our ultimate goal of personalized medicine and prevention.

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Section: Tissue and Cellular Heterogeneity: Challenges In Epigenetic mentioning

confidence: 99%

Molecular pathological epidemiology of epigenetics: emerging integrative science to analyze environment, host, and disease

et al. 2013

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“…To explore the association between methylation status in leukocyte DNA and CRC, Gao et al . found 31 CpG sites that were significantly related to CRC risk, especially at two sites in the DSP gene in male smokers 38 . The candidate biomarkers involved in our studies have been shown to be involved in multiple molecular events associated with tumorigenesis, among which IRF4 hypermethylation associated with the highest risk of CRC (OR = 16.96), while the lowest risk was seen for FOXE-1 hypermethylation (OR = 1.35).…”

Section: Discussionmentioning

confidence: 99%

Methylation of a panel of genes in peripheral blood leukocytes is associated with colorectal cancer

Luo

Huang

Sun

et al. 2016

Sci Rep

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The relationship between the DNA methylation status of the CpG islands of multiple genes in blood leukocytes in CRC susceptibility and prognosis, as well as possible interactions with dietary factors on CRC risk are unclear. We carried out a case-control study including 421 CRC patients and 506 controls to examine the associations between six genes (AOX-1, RARB2, RERG, ADAMTS9, IRF4, and FOXE-1), multiple CpG site methylation (MCSM) and susceptibility to CRC. High-level MCSM (MCSM-H) was defined as methylation of greater than or equal to 2 of 5 candidate genes (except for RARB2); low-level MCSM (MCSM-L) was when 1 candidate gene was methylated; non-MCSM was when none of the candidate genes were methylated. Blood cell-derived DNA methylation status was detected using methylation-sensitive high-resolution melting analysis. The hypermethylation status of each individual gene was statistically significantly associated with CRC. MCSM status was also associated with CRC (OR = 1.54, 95% CI: 1.15–2.05, P = 0.004). We observed interactions between a high level of dietary intake of cereals, pungent food, and stewed fish with brown sauce, age (older than 60 yrs), smoking and hypermethylation on risk of CRC. MCSM in peripheral blood DNA may be an important biomarker for susceptibility to CRC.

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“…Most mammalian DNA methylations occur on cytosine in CpG dinucleotide. CpG-rich DNA sequence known as CpG island, is mainly located in the promoter and the first exon region of a gene [11]. Except the x chromosome inactivation and the CpG island of imprinted gene, the autosomal CpG islands usually do not appear methylation.…”

Section: Discussionmentioning

confidence: 99%

A Study on the Aberrant Methylation of Colorectal Cancer MLH1 Gene

Chen¹,

Lv²,

Xu³

et al. 2019

AJCEM

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The aim of this paper is to study the mechanism of MLH1 gene expression and regulation in colorectal cancer, and to clarify the impact of 5' end CpG island aberrant methylation on the regulation of MLH1 gene expression. RT-PCR assay was used to detect the expression of MLH1 gene mRNA in 10 colon cancer cell strains. 62 fresh colorectal adenocarcinoma samples and paired distal normal mucosa were selected in our hospital. They comprised 37 males and 25 females aging 32 to 67 years old with the mean of 43.6. The cellular RNA was extracted, and immunohistochemistry assay was used to detect the expression of MLH1 protein in colorectal cancer, and MSP method was utilized to examine the methylation status of the first exon of MLH1 gene in the tissues. In the 10 cell strains, only the MLH1 mRNAs of SW480 and Caco2 were expressed, and no MLH1 mRNA expression was detected in the other eight strains. The expression level of MLH1 mRNA in the 62 cases of cancer tissue was higher than that in the paired normal mucosa, and MLH1 protein was mainly expressed in the cytoplasm. The expression level of MLH1 protein in adenocarcinoma tissues was significantly higher than that in the paired normal tissue (P<0.01), while the methylation level of cancer tissues was statistically significantly lower than that of the paired normal mucosa (P<0.05). Aberrant DNA methylation dominates the regulation of the MLH1 gene expression changes in colorectal cancer. The results herein provide a theoretical basis for clarifying the differential expressions of MLH1 in colorectal cancer in vitro and in vivo.

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Leukocyte DNA methylation and colorectal cancer among male smokers

Abstract: The results suggest that the methylation level of some genes were associated with cancer susceptibility and some were related to tumor development over time. Further studies are warranted to confirm and refine our results.

Cited by 11 publications

References 51 publications

Molecular pathological epidemiology of epigenetics: emerging integrative science to analyze environment, host, and disease

Molecular pathological epidemiology of epigenetics: emerging integrative science to analyze environment, host, and disease

Methylation of a panel of genes in peripheral blood leukocytes is associated with colorectal cancer

A Study on the Aberrant Methylation of Colorectal Cancer MLH1 Gene

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