Epigenetic dysfunctions in cancer: a cause or a consequence?
Professor Bozena Kaminska, Nencki Institute of Experimental Biology, Poland
The epigenetic landscape is deregulated in cancer due to aberrant activation/ inactivation of enzymes maintaining and modifying the epigenome. Aberrations at the global histone level and/or specific histone modifications may produce distorted patterns of gene expression and malfunction of proteins that regulate chromatin structure. Recent whole genome studies demonstrated that histones and chaperone proteins harbour mutations that may result in gross alterations of the epigenome leading to genome instability. IDH1/2 (isocitrate dehydrogenase 1/2) mutations have been detected in hematologic malignancies and certain solid tumours. Point mutations in IDH1/2 confer a gain-of-function in cancer cells, resulting in accumulation of the D-2-hydroxyglutarate (D-2HG). High levels of D-2HG interfere with cellular metabolism and epigenetic regulation by inhibiting histone and DNA demethylases, which results in blocking cellular differentiation. Histone deacetylases (HDACs) are critical regulators of gene expression that promote chromatin changes by deacetylating histones. Aberrant regulation of HDACs contributes to malignant transformation and progression in many human cancers. Dysfunction of the histone lysine methyltransferase EZH2 occurs in numerous cancers. EZH2 a part of the polycomb repressive complex 2 which catalyses trimethylation of histone H3 lysine 27. It supports undifferentiated phenotype and blocks differentiation during embryonic development and carcinogenesis. Epigenetic-based mechanisms are reversible and 'resetting' the abnormal cancer epigenome by pharmacological compounds targeting epigenetic enzymes is a promising strategy. Several novel drugs targeting tumours with mutated IDH1/2/ and numerous HDAC inhibitors have been identified. These compounds cause cell cycle arrest or death, inhibit DNA repair and some entered clinical trials for cancer treatment.
Professor Carmen Jerónimo, Portuguese Oncology Institute and University of Porto, Portugal
An increasing body of evidence is implicating several epigenetic mechanisms as driving forces of neoplastic transformation. Among these, aberrant DNA methylation is, by far, the most widely studied, followed by deregulated expression of chromatin machinery proteins and non-coding RNAs, including microRNAs. Importantly, cancer-related epigenetic alterations may provide novel cancer biomarkers, intended for early detection and diagnosis, assessment of prognosis, and prediction of response to therapy. The importance of early diagnosis in Oncology has been emphasised and although current methodologies (such as cytology, histopathology, immunohistochemistry, etc) play a critical role, molecular markers may complement or, eventually, replace them if more effective. Because epigenetic alterations often precede the emergence of the malignant phenotype, they are advantageous for early cancer detection. They might also be detected in clinical samples, including those obtained by biopsy, as well from those obtained by non-invasive methods, such as urine. Moreover, early detection of cancer relapse before it manifests clinically (or on imaging during routine patient follow-up) might be accomplished through epigenetic-based biomarkers. Some epigenetic alterations have also been associated with tumour behaviour and may, thus, serve as prognostic biomarkers.
In this talk, Professor Jerónimo will focus on the major recent findings obtained by her research team regarding epigenetic mechanisms implicated in urological tumorigenesis as well as the potential usefulness of epigenetic-based biomarkers for detection and prognostication in these cancers.
Epigenome approaches for identification of treatment resistance in cancer
Professor Lucia Altucci, University of Campania Luigi Vanvitelli, Italy
Aberrant activity of epigenetic enzymes plays a role in tumorigenesis. Reversal of these aberrant modifications has emerged as a strategy for cancer treatment. By applying epigenome-based patient stratification, the group identified a set of chromatin areas predictive for standard treatment resistance in leukaemias. Professor Altucci reports that a novel dual-epidrug, as effective in standard treatment resistant cancers. The group identified both the mechanistic insights of this action and biomarkers that might turn into a differential diagnostic tool for leukaemia patients. Together, the group provides proof of concept for the use of epigenome profiling coupled to epi-drugs to ‘personalise’ precision medicine.
Environmental metals, epigenetics and cardiovascular risk: a population-based perspective
Dr Maria Tellez-Plaza, Hospital Clinic of Valencia University, Spain; Johns Hopkins Bloomberg School of Public Health, USA
Cardiovascular disease is a major cause of mortality and morbidity world-wide. Current algorithms for cardiovascular risk prediction, which combine behavioural, clinical, and biochemical markers, are, however, of limited accuracy. Understanding novel factors and mechanisms for cardiovascular disease development can contribute to the identification of at-risk individuals, who could benefit the most from preventive interventions. Non-essential environmental metals are emerging as major contributing factors to cardiovascular health in study populations exposed to low or moderate metal dose through air, food or water. Moreover, metals accumulate in the body where they can induce long-term damages. Dr Tellez-Plaza will be discussing available evidence in support of metals as environmental determinants of both epigenetic markers and cardiovascular disease in general populations. The identification of epigenomic regions that are environmentally regulated and may be involved in pathways related to cardiometabolic risk can enable the implementation of both population-based and personalised strategies for the control of cardiovascular disease in the population. Moreover, several lines of evidence suggest that environmental exposures can influence health outcomes in subsequent generations, due to epigenetic changes. It is of interest, thus, to explore novel epigenetic approaches for prevention and treatment of disease, which may be relevant for future generations.