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

Abstract

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 neoplasms and malignancies such as 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. In particular, DNA methylation assays are widely applied to formalin-fixed, paraffin-embedded archival tissue specimens as clinical pathology tests. To better understand the interplay between etiological 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'. In contrast to traditional epidemiological 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 macroenvironment and tissue microenvironment. MPE may represent a logical evolution of GWAS, termed 'GWAS-MPE approach'. Although 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. Having a similar conceptual framework to systems biology, the holistic MPE approach enables us to link potential etiological factors to specific molecular pathology, and gain novel pathogenic insights on causality. The widespread application of epigenome (eg, methylome) analyses will enhance our understanding of disease heterogeneity, epigenotypes (CpG island methylator phenotype, LINE-1 (long interspersed nucleotide element-1; also called long interspersed nuclear element-1; long interspersed element-1; L1) hypomethylation, etc), and host-disease interactions. In this article, we 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.

Figure 1

A variety of endogenous and exogenous etiologic factors contribute to epigenetic changes leading to heterogeneity of disease processes, which is implicated by the “unique disease principle”. To simplify, only selected examples of those etiologic factors are demonstrated. There are numerous interactions between the factors, which are not depicted for simplicity.

Figure 2

Why is examining global molecular phenomena so important? A. A typical study examining the relationship between gene X hypermethylation and disease Y, or response to treatment. Global molecular features, such as CIMP status, are not often considered. B. In reality, the significant relationship, if any, between gene X hypermethylation and disease, or treatment response, may reflect the association between CIMP and disease Y, or treatment response. CIMP status always needs to be considered as a potential confounder when examining locus-specific gene promoter hypermethylation and clinical outcome. CIMP, CpG island methylator phenotype.

Figure 3

Biomarker analysis in normal tissue, stool, blood and body fluids adds new dimensions to molecular pathological epidemiology (MPE) research. Analyses of interactions among etiologic factors and biomarkers can be performed to test a specific research hypothesis.^,,,