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 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.

Long non-coding RNAs in colorectal cancer: implications for pathogenesis and clinical application

“…[40][41][42] This disease-specific focus has identified novel oncogenic drivers, and the genes contributing to functional change, 43 importantly, revealed that different molecular features contribute to individual differences that occurred in clinicopathological characteristics, disease behavior, prognosis, and response to treatments, which thus helped to establish definitions of molecular subtypes and identified new biomarkers on the basis of omic alterations. [44][45][46] It is now well known that some CRC cases are linked to some factors, such as environment, 47 inflammation, 48,49 immunity, 50 and epigenetic alterations 51,52 rather than heritable genetic changes. An interesting thing is that these factors can influence each other, for instance, epigenetic aberrations induced by environmental factors contribute to cancer processes; 53 interaction of drug and molecular characteristics can influence lncRNAs and clinical outcome; 46,54,55 and epigenetic factors such as lncRNAs can also coordinate cellular responses to environment in turn.…”

Familial colorectal cancer type X: genetic profiles and phenotypic features

“…49,51,[53][54][55][56] Global DNA hypomethylation has been associated with poor prognosis, shorter survival, younger age of onset, and familial colorectal cancer risk. 39,51,[55][56][57][58][59] The predisposition to LINE-1 hypomethylation in FCCTX tumors gives an evidence for a link between distinct molecular signatures and phenotypes associated with specific epigenotypes. 59 In hereditary colorectal cancer, relatively less is known about the patterns of specific histone modifications that also regulate gene expression through controlling chromatin conformation.…”

“…39,51,[55][56][57][58][59] The predisposition to LINE-1 hypomethylation in FCCTX tumors gives an evidence for a link between distinct molecular signatures and phenotypes associated with specific epigenotypes. 59 In hereditary colorectal cancer, relatively less is known about the patterns of specific histone modifications that also regulate gene expression through controlling chromatin conformation. 52,60 Recent studies have shown that mutation rates in colorectal cancer genomes are closely related to histone modification-directed chromatin organization and its upregulation is associated with a reduced patient survival, 52,61 suggesting a key role in colorectal cancer development.…”

Differential survival trends of stage II colorectal cancer patients relate to promoter methylation status of PCDH10, SPARC, and UCHL1

“…12 In addition to genetic changes, aberrant DNA methylation represents a hallmark of cancer and has been extensively studied in colorectal cancers. [13][14][15][16][17] Epigenetic signatures have been also shown to serve as potential diagnostic, prognostic, and predictive biomarkers (for a detailed review see Lao and Grady 18 and Ogino et al 19 ). A recurrent methylation pattern referred to as CpG island hypermethylation was initially observed by Toyota et al 20 CpG island hypermethylation has gained a broad acceptance, and although there have been conflicting results about the prognostic or predictive role of CpG island hypermethylation, 21,22 Ogino et al 7 demonstrated that CpG island hypermethylation-high status is an independent predictor of cancer survival and seems to eliminate the adverse effect of BRAF mutation, which is associated with a high mortality.…”