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Molecular Pathological Epidemiology of Epigenetics Modern Pathology (2013) 26, 465–484 & 2013 USCAP, Inc. All rights reserved 0893-3952/13 $32.00 465 Molecular pathological epidemiology of epigenetics: emerging integrative science to analyze environment, host, and disease Shuji Ogino1,2,3, Paul Lochhead3,4, Andrew T Chan5,6, Reiko Nishihara3, Eunyoung Cho6, Brian M Wolpin3, Jeffrey A Meyerhardt3, Alexander Meissner7, Eva S Schernhammer2,6, Charles S Fuchs3,6 and Edward Giovannucci2,6,8 1Department of Pathology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA; 2Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA; 3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; 4Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK; 5Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA; 6Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA; 7Broad Institute of MIT and Harvard University, Cambridge, MA, USA and 8Department of Nutrition, Harvard School of Public Health, Boston, MA, USA 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. Modern Pathology (2013) 26, 465–484; doi:10.1038/modpathol.2012.214; published online 11 January 2013 Keywords: CIMP; genetics; hypermethylation; molecular pathological epidemiology; omics; personalized therapy; unique tumor principle Correspondence: Dr S Ogino, MD, PhD, MS (Epidemiology), Epigenetic mechanisms constitute an essential Department of Epidemiology, Harvard School of Public Health, mode of gene regulation and act as an interface Department of Pathology, Brigham and Women’s Hospital, between environmental exposures, cellular re- 450 Brookline Avenue, Room JF-215C, Boston, MA 02215, USA. E-mail: [email protected] sponse, and pathological processes. DNA methyla- Received 12 September 2012; revised 5 November 2012; accepted tion level and its location constitute important gene 8 November 2012; published online 11 January 2013 regulatory mechanisms.1–4 Abnormal epigenetic www.modernpathology.org Molecular pathological epidemiology of epigenetics 466 S Ogino et al marks, including DNA methylation alterations, are a the microenvironmental changes over time. A single hallmark of most human diseases. Importantly, organ (or tissue) consists of numerous cell types epigenetic modifications are reversible, and with different epigenomes. represent potential targets for disease prevention A particular human disease process is caused by and therapy.2–6 There are other epigenetic dysfunction of a specific cell type, or multiple cell mechanisms of gene regulations, such as non- types (in one organ or across multiple organ coding RNA including microRNA.7–13 Gene systems). Thus, the optimal approach is to analyze expression levels are consequences of epigenetic molecular changes in the afflicted cell types specific regulation; however, there exists a challenge in to the disease process. To study a psychiatric or accurate quantification of transcript levels in neuronal disease, it would be best to analyze archival tissues.14 As most studies, which have disordered neurons (within the context of local examined host exposures and epigenetic alterations, microenvironment), rather than blood leukocytes or utilized DNA methylation as biomarkers, our brain tissue as a mixture of different cell types.28,29,30 discussion on previous data mostly addresses DNA Clearly, we must analyze specific cell types in each methylation. tissue in a particular microenvironmental and Accumulating evidence suggests that epigenetic disease context, using techniques such as laser aberrations induced by environmental, dietary, life- capture microdissection and flow cytometry.31,32 style, and microbial factors contribute to specific Epigenomic differences between cell types may be disease processes.15–22 To examine the complex present in a small part of the genome (with overall relationships between etiological factors, molecular similar epigenomic status); however, those minor alterations, and disease evolution, ‘molecular differences are critical in specific cell-type function pathology’ and ‘epidemiology’ have recently and disease pathogenesis, and unlikely inferred become integrated, generating the interdisciplinary from examining the epigenomes of different cell field of ‘molecular pathological epidemiology types. Although many epigenetic studies rely on (MPE)’.21–23 blood leukocytes as a surrogate for alterations As clinical molecular pathology testing is becom- in other diseased cell types,24–27,29,30–36 there is ing more and more common, we anticipate that very little evidence supporting the validity of molecular pathology data can be acumulated into inferring epigenetic mechanisms of non- disease registries around the world. This enables hematological disorders from epigenetic analysis of MPE to become routine epidemiology and pathology blood leukocytes. research practice. Thus, a role of pathologists as In contrast to non-neoplastic diseases, neoplastic educators for epidemiologists will increase. We diseases are characterized by uncontrolled cellular must emphasize pivotal roles of modern patholo- proliferation, which can provide abundant amounts gists in broader transdisciplinary biomedical of diseased cells for epigenetic analyses. We never- and public health sciences, as well as in clinical theless should note: (1) that a tumor consists of decision-making process. many different cell types (transformed neoplastic In this article, we provide an overview of the MPE cells and various non-transformed cells, such as paradigm, and proceed to illustrate the contribution fibroblasts, endothelial cells, smooth muscle cells, made by epigenetic research. While we exploit MPE and inflammatory cells), and (2) that, even within a data on neoplastic disorders, MPE approaches and single tumor, neoplastic cells are heterogeneous.37 paradigms can conceptually extend to the study of While we should be aware of these caveats, non-neoplastic diseases. neoplastic diseases still give opportunities to study epigenetic alterations in diseased cells, by providing relatively enriched disease cell population. Tissue and Cellular Heterogeneity: Challenges in Epigenetic Research In many non-neoplastic, non-hematological, non- Basic Characteristics of Disease: The dermatological diseases, access to diseased cells is Unique Disease Principle limited by current technologies.24–27 Even if tissues affected by a non-neoplastic disease (eg, inflamed Human diseases are typically very complex pro- liver) can be obtained, those tissues consist of many cesses (Figure 1), involving alterations in epigen- different cell types with varying epigenomes. omes, transcriptomes, proteomes, metabolomes, Therefore, epigenetic analysis of non-neoplastic microbiomes, and interactomes. Because each of us diseases faces a fundamental challenge of has a unique genome, and distinct combinations of heterogeneity in tissue, cells, and epigenomes, exposome,38 epigenomes, transcriptomes, proteomes, which is often overlooked or underestimated in and metabolomes in specific cell types,
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