Bio-IT World and Cambridge Healthtech Institute’s Inaugural
Clinical Epigenetics
Part of the Fifth International Clinical Genomics & Informatics Europe event
3 December 2013 | Sheraton Lisbon Hotel & Spa | Lisbon, Portugal
Recently, and fueled in part by the application of high-throughput sequencing technologies, our understanding of the disease epigenome has expanded, with the inclusion of numerous mutated genes involved in epigenetic regulation, and epimutations directly involved in producing aberrant gene expression. Epigenetic dysregulation is now a hallmark of several complex pathologies, including cancer, metabolic disorders, cardiovascular and neurological diseases, where disease-specific epigenetic signatures are now being utilized clinically for prognostics, diagnostics as well as disease-specific targeted therapy. This event is designed to unite clinicians and researchers using high-throughput technologies to explore regulatory layers above the genome, ultimately for clinical utility.
08:30 Registration and Morning Coffee
09:00 Chairperson’s Opening Remarks
Manon van Engeland, Ph.D., Professor, Department of Pathology, School for Oncology and Developmental Biology, Maastricht University Medical Center, The Netherlands
09:10 Promoter Methylation in Colorectal Cancer: Promising Clinical Applications, Challenging Translational Bottlenecks
Manon van Engeland, Ph.D., Professor, Department of Pathology, School for Oncology and Developmental Biology, Maastricht University Medical Center, The Netherlands
The epigenetic background of CRC is being unraveled rapidly. First, I will briefly review the latest data on the CRC methylome. Next, I will present the clinical relevance of methylation markers for early detection of CRC and prediction of prognosis and response to therapy in CRC. Finally, I will discuss the challenges in bringing these markers to the clinic.
09:40 DNA Methylation and Demethylation in Health and Disease
François Fuks, Ph.D., Director, Laboratory of Cancer Epigenetics, Faculty of Medicine, Free University of Brussels, Belgium
Until recently, the only known epigenetic mark on DNA in mammals was 5-methylcytosine, established and propagated by DNA methyltransferases and generally associated with gene repression. A host of new actors and novel cytosine modifications and the ten eleven translocation (TET) enzymes have appeared on the scene, sparking great interest. The challenge is now to uncover the roles they play and how they relate to DNA demethylation. Knowledge is accumulating linking these new players to essential biological processes (e.g. cell pluripotency and development) and also to cancerogenesis. We will present data highlighting new modes of action of TETs and their roles in diseases.
10:10 Long Non-Coding RNAs and the Specification of Epigenetic Modifications in Development and Disease
Marcel Dinger, Ph.D., Head, Clinical Genomics, Centre for Clinical Genomics, Garvan Institute of Medical Research, Australia
As all cells share an essentially identical genome within an individual, the specification of individual cell types is ultimately governed by epigenetic factors, which are typified by chemical modifications to histones or DNA. Although the mechanisms and protein complexes that enact such epigenetic modifications are known, it remains a mystery how these chromatin-modifying factors, which seldom possess any sequence-specificity per se, are directed with such remarkable specificity to particular sites of the genome. In this presentation, I will present evidence to support the case that long non-coding RNAs may fulfill a fundamental role in directing generic chromatin-modifying machinery to particular sites in the genome.
10:40 Coffee Break
11:10 DNA Methylation Biomarkers for Early Detection and Monitoring of Cancer
Guro Elisabeth Lind, Ph.D., Head, Epigenetics, Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Norway
By integrating large-scale analyses with detailed candidate gene characterization we aim at identifying DNA methylation biomarkers with clinical impact. A panel of methylated biomarkers suitable for detecting colorectal cancer at an early stage will be presented. In tissue samples, this panel outperforms several previously published epi-markers, including VIM and SEPT9 which are included in current non-invasive colorectal cancer tests. We are also working with urological cancers, lymphomas and cholangiocarcinomas and some of our latest data for early detection and/or monitoring of these diseases will be presented.
11:40 The Epigenetic and Genetic Context of MGMT Promoter Methylation and Its Impact on the Predictive versus Prognostic Value as a Biomarker for Glioma
Monika E. Hegi, Ph.D., Head, Laboratory of Tumor Biology & Genetics, Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois (CHUV), Switzerland
The presentation will review the predictive value of MGMT promoter methylation in glioblastoma (glioma, WHO grade IV) for benefit from alkylating agent therapy. This is a mechanistically plausible relationship due to the DNA repair function of MGMT that removes the most cytotoxic lesion introduced by alkylating agents. Surprisingly, a strong prognostic effect was observed for MGMT methylation in clinical trials with grade III glioma. The genetic and epigenetic context of this surprising, and clinically relevant difference will be discussed.
12:10 Lunch on Your Own
13:10 Session Break
14:00 Chairperson’s Opening Remarks
Guro Elisabeth Lind, Ph.D., Head, Epigenetics, Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Norway
14:05 Dynamic Changes in 5-Hydroxymethylation (5hmC) Signatures Underpin Early and Late Events in Drug Exposed Liver
Richard Meehan, Ph.D., Senior Scientist, Chromosomes and Gene Expression, Medical Research Council, The Human Genetics Unit (HGU), Western General Hospital, United Kingdom
Combined epigenomic and transcriptomic approaches can identify sets of potential biomarkers for disease progression, including cancer. Our work demonstrates that 5hmC profiling can be used as a unique indicator of cell states during organ maturation and drug-induced responses. 5hmC profiling provides novel epigenetic signatures for integrated pathway analysis and is the foundation for the epigenetics of identity.
14:35 Genome-Wide Methylation Analysis on Neuroendocrine Tumors
Christina Thirlwell, Ph.D., Senior Lecturer & Medical Oncologist, University College London, United Kingdom
Neuroendocrine tumours (NETs) are a clinically and genetically heterogeneous group of cancers with markedly different clinical outcome depending on the primary site and grade of tumour. Due to the rarity of NETs, previous genomic studies have included small sample sizes, often originating from mixed primary sites. My group has undertaken the first large scale integrated genomic analysis of pancreatic and intestinal NETs including exome sequencing, genome-wide DNA methylation analysis, RNA expression and copy number analysis. This analysis has identified disruption of the Wnt signaling and neurodevelopmental pathways in NET development. DNA methylation biomarkers (tissue based and circulating) have been identified which differentiate between normal tissue and NETs and also between histological grade of NET. Most recently we have isolated and sequenced DNA from single NET circulating tumour cells (CTCs). Analysis of this "liquid biopsy" will in the future enable us to truly personalise cancer therapy for NET patients.
15:05 Genetic Disruption of Epigenetic Enzymes in Human Disorders: Impact in Clinical Management
María Berdasco Menéndez, Ph.D., Associate Researcher, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL)
Deregulation of epigenetic profiles has been described in several human pathologies, including complex diseases (such as cancer, cardiovascular and neurological diseases), metabolic pathologies (type 2 diabetes or obesity) and a great number of rare disorders. Over the last decade it has become increasingly clear that mutations of genes involved in epigenetic mechanisms are linked to such epigenetic deregulation. We will describe some germline mutations of epigenetic modifiers that are known to be associated with human disorders (mainly cancer), and discuss their translational potential as cancer biomarkers or their impact in therapeutic strategies.
15:35 Refreshment Break
16:10 DNA Methylation in Childhood Cancer
Keith Brown, Ph.D., Reader, Molecular Pathology, School of Cellular & Molecular Medicine, University of Bristol, United Kingdom
Despite recent advances in genome sequencing, many childhood cancers lack identifiable mutations, suggesting that epigenetic alterations may play a pivotal role in pediatric cancers. We have used genome-wide DNA methylation analysis to identify epigenetic alterations in clinically important childhood cancers, specifically Wilms' tumour of the kidney and neuroblastoma, a cancer of the sympathetic nervous system. We have identified the first example of long-range epigenetic silencing in childhood cancer, as well as novel single genes that are silenced by DNA methylation. Analyses of clinically annotated patient cohorts are being used to test the diagnostic and prognostic utility of these markers. Modulators of epigenetics marks are also being employed to investigate their biological functions in cellular growth control and drug resistance.
16:35 DNA Methylation Signatures for Prediction of Biochemical Recurrence after Radical Prostatectomy of Clinically Localized Prostate Cancer
Christa Haldrup, Ph.D., Research Scientist, Department of Molecular Medicine, Aarhus University Hospital, Denmark
Through screening of prostate cancer samples and samples of adjacent normal prostate tissue, we here identify six genes (AOX1, C1orf114, GAS6, HAPLN3, KLF8, and MOB3B) which are hypermethylated in prostate cancer. Furthermore, DNA methylation of C1orf114 is significantly associated with time to PSA recurrence in multivariate cox regression analysis encompassing standard histopathological parameters in two international radical prostatectomy cohorts. Additionally we develop a dichotomized three gene DNA methylation signature which also predicts time to PSA recurrence in multivariate analysis significantly in two cohorts.This is the first study presenting a validated multi-gene DNA methylation signature as having prognostic value for radical prostatectomy patients.
17:10 Single-Cell Genomics to Study DNA-Mutation, Genetic Heterogeneity and Disease
Thierry Voet, Ph.D., Head, Laboratory of Reproductive Genomics, KU Leuven, Belgium; Associate Faculty Member, Wellcome Trust Sanger Institute
We have developed various wet-lab and computational methods that allow analyzing a solitary cell. We apply these genome-wide methods to study DNA-mutation, genetic heterogeneity and cancer. Furthermore, we developed novel generic single-cell methods for pre-implantation genetic diagnosis (PGD) of human cleavage stage embryos in the clinic.
17:35 Close of Symposium
16:00-18:00 Main Conference Registration