Epigenome dysregulation in cholangiocarcinoma

Epigenomics is a fast-evolving field of research that has lately attracted considerable interest, mainly due to the reversibility of epigenetic marks. Clinically, among solid tumors, the field is still limited. In cholangiocarcinoma (CCA) it is well known that the epigenetic landscape is deregulated both during carcinogenesis and disease progression as a consequence of aberrant mechanisms leading to genome instability. In this article, we will briefly review the molecular alterations that have been described in the transformation of normal cholangiocytes into malignant derivatives, focusing on the role of non-coding RNA (ncRNA) interactions, DNA methylation, post-translational modifications (PTMs) of histones and chromatin remodeling complexes.     

Cause and Consequences of Genetic and Epigenetic Alterations in Human Cancer

Both genetic and epigenetic changes contribute to development of human cancer. Oncogenomics has primarily focused on understanding the genetic basis of neoplasia, with less emphasis being placed on the role of epigenetics in tumourigenesis. Genomic alterations in cancer vary between the different types and stages, tissues and individuals. Moreover, genomic change ranges from single nucleotide mutations to gross chromosomal aneuploidy; which may or may not be associated with underlying genomic instability. Collectively, genomic alterations result in widespread deregulation of gene expression profiles and the disruption of signalling networks that control proliferation and cellular functions. In addition to changes in DNA and chromosomes, it has become evident that oncogenomic processes can be profoundly influenced by epigenetic mechanisms. DNA methylation is one of the key epigenetic factors involved in regulation of gene expression and genomic stability, and is biologically necessary for the maintenance of many cellular functions. While there has been considerable progress in understanding the impact of genetic and epigenetic mechanisms in tumourigenesis, there has been little consideration of the importance of the interplay between these two processes. In this review we summarize current understanding of the role of genetic and epigenetic alterations in human cancer. In addition we consider the associated interactions of genetic and epigenetic processes in tumour onset and progression. Furthermore, we provide a model of tumourigenesis that addresses the combined impact of both epigenetic and genetic alterations in cancer cells.     

Epigenetic drivers and genetic passengers on the road to cancer

Cancer is traditionally viewed as a primarily genetic disorder, however it is now becoming accepted that cancer is also a consequence of abnormal epigenetic events. Genetic changes and aneuploidy are associated with alterations in DNA sequence, and they are a hallmark of the malignant process. Epigenetic alterations are universally present in human cancer and result in heritable changes in gene expression and chromatin structure over many cell generations without changes in DNA sequence, leading to functional consequences equivalent to those induced by genetic alterations. Importantly, intriguing evidence emerged suggesting that epigenetic changes may precede and provoke genetic changes. In this scenario, epigenetic events are primary events while genetic changes (such as mutations) may simply be a consequence of disrupted epigenetic states. This fact may explain why many genetic screens proved to be limited with regard to cancer causality and pathogenesis. Aberrant epigenetic events affect multiple genes and cellular pathways in a non-random fashion and this can predispose to induction and accumulation of genetic changes in the course of tumour initiation and progression. These considerations are critical for a better understanding of tumourigenesis and molecular events underlying the acquisition of drug resistance, as well as development of novel strategies for cancer therapy and prevention.     

Distinctive patterns of DNA methylation associated with Parkinson disease

Parkinson disease (PD) is a multifactorial neurodegenerative disorder with high incidence in the elderly, where environmental and genetic factors are involved in etiology. In addition, epigenetic mechanisms, including deregulation of DNA methylation have been recently associated to PD. As accurate diagnosis cannot be achieved pre-mortem, identification of early pathological changes is crucial to enable therapeutic interventions before major neuropathological damage occurs. Here we investigated genome-wide DNA methylation in brain and blood samples from PD patients and observed a distinctive pattern of methylation involving many genes previously associated to PD, therefore supporting the role of epigenetic alterations as a molecular mechanism in neurodegeneration. Importantly, we identified concordant methylation alterations in brain and blood, suggesting that blood might hold promise as a surrogate for brain tissue to detect DNA methylation in PD and as a source for biomarker discovery.     

Epigenetic therapy of leukemia: An update

Carcinogenesis is classically thought to result from genetic alterations in DNA sequence such as deletions, mutations, or chromosomal translocations. These in turn may lead to the activation of oncogenes, inactivation of tumor suppressor genes or formation of chimeric oncoproteins. Epigenetics, in contrast, refers to a number of biochemical modifications of chromatin, either to DNA directly or to its associated protein complexes that affect gene expression without altering the primary sequence of DNA [Robertson KD, Wolffe AP. DNA methylation in health and disease. Nat Rev Genet 2000;1:11-9; Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683-92]. A fundamental difference between genetic and epigenetic alterations is the irreversible nature of genetic lesions whereas epigenetic ones are potentially reversible, allowing for therapeutic intervention. In the last decade, it has become apparent that epigenetic changes play an important role in cancer, particularly in leukemia. Significant advances have been made in the elucidation of these processes as well as in translating this knowledge to the clinic, as in the development of new prognostic biomarkers or targeted therapies. In this review, we will focus on recent advances in epigenetic therapy in leukemia.     

Epigenetic deregulations in chordoma

Chordoma is a rare type of malignant bone tumour arising from remnant notochord and prognosis of patients with it remains poor as its molecular and genetic mechanisms are not well understood. Increasing evidence has demonstrated that epigenetic mechanisms (DNA methylation, histone modification and nucleosome remodelling), play a crucial role in the pathogenesis of many diseases. Aberrant epigenetic patterns are present in patients with chordoma, indicating a potential role for epigenetic mechanisms inthis malignancy. Furthermore, epigenetic alterations may provide novel biomarkers for diagnosis and prognosis as well as therapeutic targets for treatment. In this review, we discuss relevant epigenetic findings associated with chordoma, and their potential application for diagnosis, prognosis and treatment.     

Genetic and epigenetic alterations in pancreatic carcinogenesis

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Despite significant progresses in the last decades, the origin of this cancer remains unclear and no efficient therapy exists. PDAC does not arise de novo: three remarkable different types of pancreatic lesions can evolve towards pancreatic cancer. These precursor lesions include: Pancreatic intraepithelial neoplasia (PanIN) that are microscopic lesions of the pancreas, Intraductal Papillary Mucinous Neoplasms (IPMN) and Mucinous Cystic Neoplasms (MCN) that are both macroscopic lesions. However, the cellular origin of these lesions is still a matter of debate. Classically, neoplasm initiation or progression is driven by several genetic and epigenetic alterations. The aim of this review is to assemble the current information on genetic mutations and epigenetic disorders that affect genes during pancreatic carcinogenesis. We will further discuss the interest of the genetic and epigenetic alterations for the diagnosis and prognosis of PDAC. Large genetic alterations (chromosomal deletion/amplification) and single point mutations are well described for carcinogenesis inducers. Mutations classically occur within key regions of the genome. Consequences are various and include activation of mitogenic pathways or silencing of apoptotic processes. Alterations of K-RAS, P16 and DPC4 genes are frequently observed in PDAC samples and have been described to arise gradually during carcinogenesis. DNA methylation is an epigenetic process involved in imprinting and X chromosome inactivation. Alteration of DNA methylation patterns leads to deregulation of gene expression, in the absence of mutation. Both genetic and epigenetic events influence genes and non-coding RNA expression, with dramatic effects on proliferation, survival and invasion. Besides improvement in our fundamental understanding of PDAC development, highlighting the molecular alterations that occur in pancreatic carcinogenesis could provide new clinical tools for early diagnosis of PDAC and the molecular basis for the development of new effective therapies.     

Disruption of Dnmt1/PCNA/UHRF1 Interactions Promotes Tumorigenesis from Human and Mice Glial Cells

Global DNA hypomethylation is a hallmark of cancer cells, but its molecular mechanisms have not been elucidated. Here, we show that the disruption of Dnmt1/PCNA/UHRF1 interactions promotes a global DNA hypomethylation in human gliomas. We then demonstrate that the Dnmt1 phosphorylations by Akt and/or PKC abrogate the interactions of Dnmt1 with PCNA and UHRF1 in cellular and acelluar studies including mass spectrometric analyses and the use of primary cultured patient-derived glioma. By using methylated DNA immunoprecipitation, methylation and CGH arrays, we show that global DNA hypomethylation is associated with genes hypomethylation, hypomethylation of DNA repeat element and chromosomal instability. Our results reveal that the disruption of Dnmt1/PCNA/UHRF1 interactions acts as an oncogenic event and that one of its signatures (i.e. the low level of mMTase activity) is a molecular biomarker associated with a poor prognosis in GBM patients. We identify the genetic and epigenetic alterations which collectively promote the acquisition of tumor/glioma traits by human astrocytes and glial progenitor cells as that promoting high proliferation and apoptosis evasion.     

The epigenetic face of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an archetypical systemic, autoimmune inflammatory disease characterized by the production of autoantibodies to multiple nuclear Ags. Apoptotic defects and impaired removal of apoptotic cells contribute to an overload of autoantigens that become available to initiate an autoimmune response. Besides the well-recognized genetic susceptibility to SLE, epigenetic factors are important in the onset of the disease, as even monozygotic twins are usually discordant for the disease. Changes in DNA methylation and histone modifications, the major epigenetic marks, are a hallmark in genes that undergo epigenetic deregulation in disease. In SLE, global and gene-specific DNA methylation changes have been demonstrated to occur. Moreover, histone deacetylase inhibitors reverse the skewed expression of multiple genes involved in SLE. In the present study, we discuss the implications of epigenetic alterations in the development and progression of SLE and how epigenetic drugs constitute a promising source of therapy to treat this disease.     

Translational application of epigenetic alterations: ovarian cancer as a model

Cancer is a disease initiated and driven by the accumulation and interplay of genetic and epigenetic mutations of genes involved in the regulation of cell growth and signaling. Dysregulation of these genes and pathways in a cell leads to a growth advantage and clonal expansion. The epigenetic alterations involved in the initiation and progression of cancer are DNA methylation and histone modifications which interact to remodel chromatin, as well as RNA interference. These alterations can be used as candidate targets in molecular tests for risk, early detection, prognosis, prediction of response to therapy, and monitoring, as well as new therapeutic targets in cancer. In this review, we discuss the rationale, studies to date, and issues in the translational application of epigenetics using epithelial ovarian cancer as a specific example of all types of cancer.     

Epigenetic and genetic burden measures are associated with tumor characteristics in invasive breast carcinoma

The development and progression of invasive breast cancer is characterized by alterations to the genome and epigenome. However, the relationship between breast tumor characteristics, disease subtypes, and patient outcomes with the cumulative burden of these molecular alterations are not well characterized. We determined the average departure of tumor DNA methylation from adjacent normal breast DNA methylation using Illumina 450K methylation data from 700 invasive breast tumors and 90 adjacent normal breast tissues in The Cancer Genome Atlas. From this we generated a novel summary measure of altered DNA methylation, the DNA methylation dysregulation index (MDI), and examined the relation of MDI with tumor characteristics and summary measures that quantify cumulative burden of genetic mutation and copy number alterations. Our analysis revealed that MDI was significantly associated with tumor stage (P = 0.017). Across invasive breast tumor subtypes we observed significant differences in genome-wide DNA MDIs (P = 4.9E–09) and in a fraction of the genome with copy number alterations (FGA) (P = 4.6E–03). Results from a linear regression adjusted for subject age, tumor stage, and estimated tumor purity indicated a positive significant association of MDI with both MCB and FGA (P = 0.036 and P < 2.2E–16). A recursively partitioned mixture model of all 3 somatic alteration burden measures resulted in classes of tumors whose epigenetic and genetic burden profile were associated with the PAM50 subtype and mutations in TP53, PIK3CA, and CDH1. Together, our work presents a novel framework for characterizing the epigenetic burden and adds to the understanding of the aggregate impact of epigenetic and genetic alterations in breast cancer.     

Epigenetic Modulation in Parkinson’s Disease and Potential Treatment Therapies

In the recent past, huge emphasis has been given to the epigenetic alterations of the genes responsible for the cause of neurological disorders. Earlier, the scientists believed somatic changes and modifications in the genetic makeup of DNA to be the main cause of the neurodegenerative diseases. With the increase in understanding of the neural network and associated diseases, it was observed that alterations in the gene expression were not always originated by the change in the genetic sequence. For this reason, extensive research has been conducted to understand the role of epigenetics in the pathophysiology of several neurological disorders including Alzheimer’s disease, Parkinson’s disease and, Huntington’s disease. In a healthy person, the epigenetic modifications play a crucial role in maintaining the homeostasis of a cell by either up-regulating or down-regulating the genes. Therefore, improved understanding of these modifications may provide better insight about the diseases and may serve as potential therapeutic targets for their treatment. The present review describes various epigenetic modifications involved in the pathology of Parkinson’s Disease (PD) backed by multiple researches carried out to study the gene expression regulation related to the epigenetic alterations. Additionally, we will briefly go through the current scenario about the various treatment therapies including small molecules and multiple phytochemicals potent enough to reverse these alterations and the future directions for a better management of PD.

     

Mechanisms and consequences of somatic mosaicism in humans

Somatic mosaicism -- the presence of genetically distinct populations of somatic cells in a given organism -- is frequently masked, but it can also result in major phenotypic changes and reveal the expression of otherwise lethal genetic mutations. Mosaicism can be caused by DNA mutations, epigenetic alterations of DNA, chromosomal abnormalities and the spontaneous reversion of inherited mutations. In this review, we discuss the human disorders that result from somatic mosaicism, as well as the molecular genetic mechanisms by which they arise. Specifically, we emphasize the role of selection in the phenotypic manifestations of mosaicism.     

Initiation of aberrant DNA methylation patterns and heterogeneity in precancerous lesions of human hepatocellular cancer

While intratumor heterogeneity contributes to disease progression, metastasis, and resistance to chemotherapy, it also provides a route to understanding the evolution and drivers of disease. Defects in epigenetic landscapes are intimately linked to pathogenesis of a variety of human diseases, with epigenetic deregulation promoting tumorigenesis. Understanding epigenetic heterogeneity is crucial in hepatocellular carcinoma (HCC), where epigenetic alterations are frequent, early, and pathogenic events. We determined genome-wide DNA methylation and copy number variation leveraging the Infinium 450K in a series of regenerative nodules from within single patient livers. Bioinformatics strategies were used to ascertain within-patient heterogeneity, link epigenetic changes to clinical features, and determine their relevance to disease pathogenesis. Our data demonstrate that DNA methylation and copy number alterations evolve during the pre-neoplastic phase of HCC and independently segregate regenerative nodules into distinct clusters. Regenerative nodules with a high frequency of epigenetic changes have significantly lower copy number variation, suggesting that individual nodules have differential enrichment of epigenetic and genetic components, with both contributing to disease progression. Regenerative nodules were scored based on ‘epigenetic progression’ with higher scores associated with increased proliferation measured by Ki67 staining. Early events observed in epigenetically ‘aggressive’ nodules are enriched for genes involved in liver cancer. Our study demonstrates that marked epigenetic and genetic heterogeneity exists in early pre-neoplastic liver tissue within individual patients, emphasizing the potential contributions of each mechanism to driving liver disease progression, and it unveils strategies for identifying epigenetic drivers of hepatocellular carcinoma.     

DNA methylation in endometrial cancer

Endometrial cancer is the most commonly diagnosed gynecological cancer, and it has been shown to be a complex disease driven by abnormal genetic, and epigenetic alterations, as well as environmental factors. Epigenetic changes resulting in aberrant gene expression are dynamic and modifiable features of many cancer types. A significant epigenetic change is aberrant DNA methylation. In this review, we review evidence on the role of aberrant DNA methylation, examining changes in relation to endometrial carcinogenesis, and report on recent advances in the understanding of the contribution of aberrant DNA methylation to endometrial cancer with the emphasis on the role of dietary/ lifestyle and environmental factors, as well as opportunities and challenges of DNA methylation in endometrial cancer management and prevention.     

Epigenetic modifications and human disease

Epigenetics is one of the most rapidly expanding fields in biology. The recent characterization of a human DNA methylome at single nucleotide resolution, the discovery of the CpG island shores, the finding of new histone variants and modifications, and the unveiling of genome-wide nucleosome positioning maps highlight the accelerating speed of discovery over the past two years. Increasing interest in epigenetics has been accompanied by technological breakthroughs that now make it possible to undertake large-scale epigenomic studies. These allow the mapping of epigenetic marks, such as DNA methylation, histone modifications and nucleosome positioning, which are critical for regulating gene and noncoding RNA expression. In turn, we are learning how aberrant placement of these epigenetic marks and mutations in the epigenetic machinery is involved in disease. Thus, a comprehensive understanding of epigenetic mechanisms, their interactions and alterations in health and disease, has become a priority in biomedical research.