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Potential etiologic of the epigenetic field defect in the diseases and in cancer
Giorgio Malpeli
Department of Surgery and Oncology, the Hospital and University of Verona, Verona, Italy; 2Department of Pathology, the Hospital and University of Verona, Verona, Italy.

Article ID: 100004P03GM2015

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Giorgio Malpeli
Department of Pathology and Diagnostics , PiastraOdontoiatrica
2° piano, Piazzale L.A. Scuro
10, Verona
Italy, 37134
Phone: +39 0458126727
Fax: +39 0458027136

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Malpeli G. Potential etiologic of the epigenetic field defect in the diseases and in cancer. Edorium J Pathol 2015;2:10–13.

Genome-wide association studies in diseases and cancer

The genomic era has brought to a great advance in our understanding of the molecular basis of diseases. Genome wide association studies (GWAS) has provided a comprehensive map of genetic susceptibility to some complex diseases [1] [2]. However, only a minority of diseases are associated with single nucleotide mutations, deletions, amplifications or polymorphisms. Recently, results of GWAS studies on many cancer types have been published and forthcoming, for example pancreas, gastric, prostate, breast, colon, and acute lymphoblastic leukemia [3] [4] [5] [6] [7] [8].

Field defect concept

Different interpretations were proposed to explain the ineffectiveness of GWAS in many diseases, including untested rare variants, and gene-gene and gene-environment interactions [9]. One explanation was based on the epigenetic theory, which hypothesized that the epigenome is an interface between genome and environment to adjust the phenotype. The epigenetic code includes both methylation at cytosine in CpG site of DNA and covalent modifications of chromatin-associated proteins with regulatory properties on gene transcription [10]. In pathology, the theory of the field defect assumes that a local modification occurring in a tissue may anticipate the onset of a pathological condition, having potentially a causative role. The epigenetic marks meet the concept of field: they persist during the development of a cell type; if transmitted to offspring, they contribute to the generation of the wide range of different phenotypes and epigenomes with same genotype [11]. Epigenetic map can evolve during cell lifetime and influence the expression of the genome. Thus, the epigenetic changes transferred to daughter cells may potentially determine the inception of a silent field defect, even in the absence of cytological abnormalities.

Epigenome-wide association studies in diseases

Epigenome-wide association studies (EWAS) hold promise for the detection of new regulatory mechanisms that may be susceptible to modification by environmental and lifestyle factors affecting proneness to disease. One hundred and eleven different primary cells were profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression, providing references resource for interpreting the molecular basis of human diseases [11]. Global epigenetic patterns were used to identify risk factor in exogenous factors as smoking, diet, medication, senescence, endogenous factors as senescence, and pathological factors as inflammation, arthritis, autoimmune diseases, chronic diseases and other types of diseases [12].

Interplay between genetics and epigenetics

The exogenous and endogenous agents able to induce epigenetic and genetic damages have been demonstrated to be major causes of diseases and cancer [13]. The epigenetic changes have gathered much attention as a pivotal player in aging, tissue atrophy, age-related neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, as well as in autoimmune diseases [14]. In this contexts, the epigenome could mediate interactions between genetic and environmental risk factors, or directly interact with pathological factors. Autoimmune diseases as systemic lupus erythematosus (SLE) and rheumatoid arthritis, unrelated to date with mutations in the DNA methylation machinery, showed epigenetic disorder characterized by global hypomethylation and local hypermethylation in the promoter of some genes. The mechanism responsible for the widespread hypomethylation involved the loss of DNMT1 expression [15]. It is come to attention the role of genetic variability in determining epigenetic profiles [16][17]. The interplay between genetics and epigenetic aspects is a key goal for the comprehension of aetiology of diseases.

Field defect in cancer

Epigenome-wide association studies (EWAS) were performed in various cancer types mainly by comparing cancer tissues with adjacent tumor-free tissue [18]. However, cancerous organs may exhibit epigenetic changes even in regions with histologically normal tissue, making organ tissue from healthy control subjects a preferable choice for epigenetic studies [19] [20]. A frequent early alteration found in normal tissue adjacent to cancer is the expression deficiency of proteins involved in DNA repair (mutator phenotype). This type of abnormality is a prototypical field defect, as it predisposes normal cells to accumulate secondary genetic and epigenetic changes and finally to become genetically unstable. For example, methylation of MGMT, a gatekeeper DNA repair enzyme that removes mutagenic and cytotoxic adducts from the O6-guanine in DNA, was found in several sporadic cancer types and also in normal tissues adjacent and far to cancer sites in the same tissues [21] [22].

Epigenetic mechanisms promote the switch among transcriptional variants expressed at gene loci [23] [24] [25] [26]. The expression switch from isoform M1 of the PKM2 (pyruvate kinase) gene to the isoform M2 in glioblastoma, a mediator of the Warburg effect in tumor, correlated with hypomethylation of M2 promoter [23].

Epigenetic origins of the field defect in cancer

The actual models of cancer onset predict that pro-tumorigenic mutations unable to produce morphological change can predispose to cancer formation. It is thought that genome wide hypomethylation and local hypermethylation in the CpG islands of specific gene promoters precede the cell transformation process towards a neoplasia and accumulation of genetic alterations [27] [28].

Several studies have identified genetic and epigenetic alterations in apparently normal mucosa of colorectal cancer patients [20] [27][29]. The synchronous colorectal carcinomas provide a model to study the contribution of epigenetic mechanisms to field cancerization [30]. LINE-1 hypomethylation in non-cancerous colonic mucosa demonstrated to be an epigenetic predictive biomarker for multiple colorectal cancer risk. Later, it was demonstrated that at least a proportion of sporadic colorectal cancers displays a CpG island methylator phenotype (CIMP) [31]. However, this unique methylation phenotype plays a role in different cancer types. CIMP-positive tumors exhibit common molecular and clinicopathological characteristics, suggesting that CIMP represents a distinct cross-cancer carcinogenic pathway [32] .

External signals and the microenvironment can perturb cell homeostasis by inducing epigenome changes and a field defect predisposing to diseases. Ultraviolet light exposure demonstrated to be etiopathological agent of premalignant and malignant skin cancer formation. UVA light exposure induces radical oxygen species and the activation of several signal cascades, as increased AP-1 and matrix metalloproteinase expression, impaired TGF-beta signaling, enhanced collagen degradation, and decreased collagen synthesis [33]. In addition, oxidative damages lead to recruitment of DNMT1 and DNMT3B protein to damaged sites and hypermethylation of selected CG-rich promoters [34] [35] A significant advance in the comprehension of skin cancerization was provided by studies on an animal model lacking the CSL gene, a component of the Notch signaling pathway, in mesenchymal cells [36]. In this model, dermal atrophy and inflammation were precursor lesions anticipating cell transformation to skin cancer activated by UVA treatment. In human fibroblasts, the loss of Notch2 due to hypermethylation at atrophic and inflamed skin areas duplicated the phenotype CSL-null [36]. These data suggest that a field of cancerization can emerge by defects of the cell-to-cell interactions mediated by epigenetic changes which alter the Notch signaling pathway.

Epigenetic complexity and perspectives

The results of the work of Kaz et al. 2014 [27] and Subramaniam et al. 2014 [20] on colon cancer open further levels of complexity for the definition of epigenetic field defect. In fact, the spread of methylation varied according with the anatomical location of the sampling and the distance from cancer location. These evidences suggest that a more precise comprehension of the pathogenetic role of epigenetic mechanisms in cancer onset requires longitudinal studies able to depict step by step the cancerization of specific districts of a tissue.

A field defect mediated by epigenetic changes can arise in any cell type, promoting degeneration and cancerization. We are in the phase of learning how aberrant placement of the epigenetic marks and alterations of the epigenetic machinery are involved in diseases. A comprehensive understanding of epigenetic mechanisms, their interactions, and the interplay of epigenetic and genetic studies, in health and disease represent a priority in the biomedical research.

Keywords: Epigenetic field defect, Cancer, Genetic damages, Autoimmune diseases

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Author Contributions:
Giorgio Malpeli – Substantial contributions to conception and design, Acquisition of data, Analysis and interpretation of data, Drafting the article, Revising it critically for important intellectual content, Final approval of the version to be published
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The corresponding author is the guarantor of submission.
Source of support
Conflict of interest
Authors declare no conflict of interest.
© 2015 Giorgio Malpeli. This article is distributed under the terms of Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium provided the original author(s) and original publisher are properly credited. Please see the copyright policy on the journal website for more information.

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