Wednesday 3 October The last day of conference was devided in two sessions, focusing on implementation of personalised medicine in clinical practice. Session 8: PHARMACOGENOMICS: CHALLENGES OF CLINICAL TRANSLATION Chairs: Urs Meyer, Basel, Switzerland / Charity Nofziger, Salzburg, Austria The first session of the day started with a lecture of Federico Innocenti (Chapel Hill, United States), who discussed the role of genomics in safety of drug treatment in oncology (6). He reminded the audience the importance of the effect that adverse events have on drug treatment in cancer. Not only they have a significant burden on the quality of life of the patient and the families, but they also reduce confidence in the treatment and often lead to permanent discontinuation of therapy. However, genetic analyses can increase patient safety and have the potential of improving safety of cancer drugs in several ways. These aspects are of particular importance for implementation, as access to genetic profiling is becoming more common for patients. Commonly, drugs frequently associated with adverse events are known to be metabolized by enzymes with genetic polymorphisms. Genetic analysis of patients using such treatment is therefore of crucial importance to prevent possible adverse events. CYP2D6 is responsible for metabolizing around 25% of clinically prescribed drugs, and is riddled with function altering variations, including point mutations, insertions and deletions, as well as hybrid formation with its pseudogene, CYP2D7—all of which make accurate genotyping quite challenging (8). In the following speech, Charity Nofziger (Salzburg, Austria) presented the technical challenges in CYP2D6 analysis, focusing on allele drop-out events that can severely alter the prediction of metabolizing phenotypes within a particular patient. Urs A. Meyer (Basel, Switzerland) continued the debate with an overview of present studies on clinical implementation of digital signatures of the drug response profiles. In most therapies, efficacy and toxicity is determined by the combined action of multiple genetic, epigenetic, environmental and host factors, and the genetic contribution may be too small for predicting drug response. Therefore, application of “-omics”-based data in combination with clinical and environmental factors to predict an individual’s drug response is one of the visions of pharmacogenomics, personalised medicine and precision medicine. For an increasing number of actionable gene-drug interactions, practice guidelines based on genetic and clinical information have been established (http://cpicpgx.org). The incorporation of pharmacogenetic test results, combined with clinical decision support (CDS) into machine-readable electronic medical records (EMRs) allows clinical implementation of this information. In the view of the above, Urs A. Meyer discussed how to best apply the already existing digital genomic and other “-omics” information to optimize drug response. Belgin Süsleyici (Istanbul,Turkey) presented an example of implementation of pharmacogenetics in Turkish clinical practice, focusing on enzyme dihydropyrimidine dehydrogenase (DPD). DPD is important catalyzer of fluorouracil metabolism, a common drug for treatment of colorectal carcinoma. However, individuals carrying at least 1 copy of no function DPYD variant may not be able to metabolize fluorouracil at normal rates and are at risk of life threatening toxicity. In a recent research, associations between fluorouracil treatment outcomes and germ line polymorphisms in DPYD were analysed. Belgin Süsleyici demonstrated that the variances of the DPYD gene can have no functional consequences on enzymatic activity, can decrease or increase metabolism of the drug. She concluded that clinicians should be strongly encouraged to consider testing for DPD poor metabolizer variants as a rational pre-treatment screening for patient candidates to a fluoropyrimidine-based therapy, in order to prevent toxicities and personalised treatments. For the closure of the session, Alexander Jetter (Zurich, Switzerland) shared his views on pharmacogenetics as the basis of individualized therapy decisions. Session 9: WHAT CAN WE LEARN FROM ELECTRONIC HEALTH RECORDS? Chairs: Panagiotis Deloukas, London, United Kingdom / Markus Paulmichl, Salzburg, Austria The final session was introduced by Rong Chen (Mount Sinaï, United States), who discussed how to use Big Data to interpret genomes to accelerate drug discovery. He is the principal investigator in The Chen Lab, consecrated to translational bioinformatics and personalised medicine. In his lab they are integrating genome sequencing, exome sequencing, and RNA-Seq data to drive personalised cancer therapy. Harry Hemingway (London, United Kingdom) continued the session with a presentation of Large-scale enquiry of longitudinal electronic health records (EHR), linked to genomic and “-omics” resources (14). Such resources can offer discovery science with well-established designs, improve care through preventive genomics and provide new kinds of scientific enquiry based on an agnostic understanding of longitudinal human phenome sequences. He presented the national platform CALIBER (www.ucl.ac.uk/health-informatics-caliber) that developed phenotyping algorithms for 72 diseases and risk factors and made them available through an open-access Data Portal, together with a set of open source tools. He concluded that in the era of precision medicine, robust approaches to creating, validating and sharing EHR-derived phenotypes are critical to enable cross-source analyses of thousands of simple and complex traits in millions of individuals. The CALIBER approach provides a transparent methodology for transforming raw EHR to reproducible phenotypes for use in such studies. Richard Trembath (London, United Kingdom) introduced East London Genes & Health cohort, containing primary health data of over 20,000 people, aiming to improve health among people of Pakistani and Bangladeshi heritage in East London by analyzing the genes and health of local people. The last presentation of the conference was given by Panagiotis Deloukas (London, United Kingdom), who shared his experiences of linking genetic data to risk of recurrent cardiovascular events through hospital records. So far, 70 loci were associated with coronary heart disease and myocardial infraction and are currently undertaking further analyses in UK Biobank including gene-gene and gene-environment interactions, together with integrated approach of using CHD risk factors such as lipid levels, blood pressure, haematological traits, and height through QTL analyses in large, well-phenotyped cohorts with an ultimate goal of developing a risk model for recurrent MI and test its clinical utility. CONCLUSIONS & PERSPECTIVES REMARKS Conference officially finished with conclusions and perspective remarks given by Sofia Siest (Nancy, France) and Urs Meyer (Basel, Switzerland).
Tuesday 2 October The third day of the conference highlighted the benefits and challenges of use of pharmacogenomics data in diagnostics and treatment, with a special focus in fields with biggest perspective for a future development. Session 5: GENE-ENVIRONMENT INTERACTIONS IN CARDIO-METABOLIC DISEASES AND CANCER Chairs: Robert Barouki, Paris, France / Michael Marschler, Mannheim, Germany Georges Dedoussis (Athens, Greece) inaugurated the third day of conference with presentation of nutrigenetics in non-alcoholic fatty liver disease (NAFLD). This disease is primarily activated by dietary factors, obesity and insulin resistance, however, polygenic background is believed to impact susceptibility to the onset and progression of NAFLD. Therefore, the study of gene-diet interactions that lead to NAFLD onset and progression became an important subject of the research and key to enable the application of personalised nutrition and thus provide patients with more efficient therapies. Georges Dedoussis illustrated the lecture with interesting examples of acquired knowledge: diet with increased fish intake that would normally be considered as healthy, resulted in increased intrahepatic accumulation of triglycerides for the carriers of a TM6SF2 variant, one of the four genetic variants that have been identified as risk factors for NAFLD. Such findings demonstrate the importance of nutrigenetics research and application of the right diet for the patients with NAFLD. Hugues Aschard (Paris, France) explained theoretical aspects of interaction tests in regression models with the use of real data example, including breast cancer, to illustrate the potential impact of right understanding of statistical analysis on detection and clinical utility of data. He showed that the simplest biological interaction models—in which the magnitude of a genetic effect depends on a common exposure—are among the most difficult to identify. Moreover, he presented new insights on advantages and limitations of multivariate interaction models that can be leveraged for future method development and for improvement of our understanding of the interplay between genetic variants and environmental exposures in multifactorial traits and diseases. Identifying precise and predictive biomarkers of health and disease is a critical objective of clinical biochemistry and biomedical research. Robert Barouki (Paris, France) introduced new concepts and technologies in exposome studies and epigenomics, which could be used to support preventive action in medicine (4). Research in the exposome field allowed the development of sensors and biological biomarkers using “-omics” technologies that can support the prediction of the effect of those exposures on human health. He highlighted the utility of integration of genome, epigenome and exposome data to generate precise observations that could be of value for prevention. Session 6: LATEST INSIGHTS IN STROKE: CLINICAL TRIALS AND APPLICABILITY OF ‘-OMICS’ DATA IN PATIENT’S STRATIFICATION Chairs: John Lamont, Crumlin, County Antrim, United Kingdom / Federico Innocenti, Chapel Hill, United States As in many diseases, response to treatment in stroke differs from one individual to another. Pharmacogenetics aims to stratify patients based on their genetic information into groups that are more likely to benefit from a particular intervention, in order to select appropriate treatments. Increased understanding of stroke pharmacogenetics has been driven by advances in genotyping technology and increased interest in developing targeted pharmaceutical treatments. Guillaume Pare (Ontario, Canada) summarized the pharmacogenetics of stroke by providing an overview of the genetic variants that contribute to the individual responses to aspirin, clopidogrel, warfarin and dabigatran and discussed considerations for evidence-based implementation. He suggested that reasons for limitations in implementation of pharmacogenetics in clinical settings can be found in the lack of awareness and need for evidence-based recommendations. Alexander Haliassos (Athens, Greece) continued the discussion on stroke, mainly focusing in protein biomarkers in diagnosis of ischemic stroke (5). Fast and accurate diagnosis of patients is crucial, but challenging, since ischemic stroke cannot be identified based only on clinical assessment. New non-invasive tests that could quickly distinguish stroke from stroke mimics and ischemic from hemorrhagic stroke would be a good alternative to CT or MRI imaging. Alexander Haliassos suggested that identification of blood biomarkers of stroke is a perspective area of research, since their potential use is not limited to diagnosis and differentiation, but can be applied to prognosis and patient treatment monitoring. However, he pointed out factors that are limiting such researches: heterogeneity and complexity of stroke etiology, analytical issues and difficulties at the interpretation of laboratory measurements. To the date, many biomarkers have been identified, but none so far has shown sufficient sensitivity and specificity to be used in the clinical setting. RANDOX WORKSHOP Randox is a world leader in the in-vitro diagnostics industry, offering most comprehensive insight into patient diagnosis allowing for more effective disease management and treatment. The company developed Biochip Array Technology (BAT), which is capable of simultaneous multi-analyte diagnostic testing within the fields of clinical research and drugs of abuse testing. Cliona Johnston (Crumlin, County Antrim, United Kingdom) presented new possibilities for clinical evaluation of the type 1 diabetes based on genetic risk evaluation, using the innovative Biochip Array Technology. CLOSED MEETING – VEGF CONSORTIUM The members of VEGF consortium gathered together in a closed meeting. They have discussed the past work of the consortium and future projects, aiming to maintain and further develop the transnational collaborative network, dedicated to large integrative and multidisciplinary genomic studies of the Vascular Endothelial Growth Factor, in order to generate applicable knowledge for medical practice. ILLUMINA WORKSHOP Medical progress is vastly depended on tight collaboration between academy, hospitals and industry. Illumina is one of the enterprises that is strongly involved in genetics and pharmacogenomics studies. The expert in pharmacogenomics Ron Van Schaik (Rotterdam, The Netherlands) discussed his experiences with pharmacogenetics using the Illumina GSA array. His speech was followed by presentation of Lili Milani (Tartu, Estonia) on Estonian personalised medicine initiative: calculation of polygenic risk scores, pharmacogenetics and rare mutations. Session 7: PAIN MANAGEMENT - A ‘JOURNEY’ FROM ‘CLINICAL TRIAL’ VIA ‘POST- MARKETING PHARMACOVIGILANCE / RISK MANAGEMENT’ TO ‘SUCCESS STORY’ Chairs: Michael Marschler, Mannheim, Germany / Lynn Webster, Salt Lake City, United States The afternoon session started with the journey towards successful pain management with genetic biomarkers as common denominators for specific pain disorders, presented by Lynn Webster (Salt Lake City, United States). She described the study of “-omics” biomarkers that contribute to the risk of developing and severity of chronic low back pain (CLBP), which is a part of PainOMICS project funded by European Community. Designed as an international retrospective observational case-control clinical study, it aims to determine “-omics” biomarkers, potentially associated with susceptibility to CLBP as well as to recognize genetic variants associated with persistent CLBP, by comparing patients having CLBP and pain-free patients. As this is an ongoing study, no result has been published so far. Laure Elens (Brussels, Belgium) took over the sails and presented pharmacogenetics of opioid treatments. Inter-individual differences in sensitivity to pain can be very problematic, especially during medical interventions and in managing discomfort after medical intervention. However, there is the evidence that genetic variations and SNPs in genes, implicated in the opioid response pathway or the mechanisms of pain sensing, might explain the various phenotypes related to pain susceptibility and response to opioid therapy. In her presentation, she summarized current knowledge in opioid pharmacogenetics and possible beneficial applications in clinical practice to allow better individualization of pain discomfort, when treated with opioids. Noelia Martin Granado (Madrid, Spain) continued the session with a talk about pharmacogenomics in post-marketing pharmacovigilance. Firstly, she reminded the audience that pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of Adverse Drug Reactions (ADRs). Since there is strong evidence that genomic factors may play a key role in the pathogenesis of both predictable and idiosyncratic ADRs, it is not surprising that pharmacovigilance activities are informed and guided by accompanying pharmacogenomics analyses. Overall, this presentation offered a review of the potential for developing specific pharmacogenovigilance programs by integrating pharmacogenomics with pharmacovigilance, with a special focus on PRA Pharmacogenomics Working Group experience. She concluded that the great potential of pharmacogenomics in reducing the occurrence of ADRs justifies the need of developing new pharmacogenovigilance strategies to better personalize drug treatment, to refine the current post-marketing drug safety surveillance and to optimally safeguard patient health. The finishing lecture of the session was given by Andrew Purchase (Swansea, United Kingdom), who discussed how the adoption of pharmacogenomics leads to patient benefit. He provided an overview of the increasing acceptance and adoption of pharmacogenomics into clinical practice, and how this translates into benefits for the patient. The presentation also explored methodologies for raising patient awareness and understanding of the potential benefits linked to pharmacogenomics, as well as current/future technologies that support the use of genomic data.
Monday 1, October The second day of the conference offered four sessions with the main focus in patient data; benefits of collecting new information from big cohort studies, usage of patient data in diagnostics and treatment, and importance of standardization of procedures, intended for collection and utilization of patient data. Session 1: “-OMICs” BIOMARKERS COMMONaliTy in Cardio-metabolic diseases and cancer – Can sequencing offer a diagnosis? Chairs: Panagiotis Deloukas, London, United Kingdom / Heiko Meyer, Hamburg, Germany The session started with the morning lecture, given by Christopher B. Newgard (Durham, United States), who discussed the application of metabolomics and other “-omics” tools for understanding of mechanisms contributing to pandemic metabolic diseases of our era – diabetes, obesity, and cardiovascular disease (1). With the practical examples from the investigation of the mechanistic and therapeutic significance of a metabolomics signature of perturbed branched chain amino acid (BCAA) catabolism in multiple cohorts of insulin resistant humans, compared to normally insulin sensitive controls (2), Dr. Newgard demonstrated the potential of metabolic profiling for defining novel metabolic disease mechanisms and new therapeutic strategies. Next, two remarkable project that evolved the era of genomics were presented. Firstly, Mark Caulfield (London, United Kingdom) gave the speech on 100,000 Genomes Project and its impact on transforming genomics in healthcare. In the frames of the project, thirteen NHS Genomic Medicine Centres of excellence across England were created in the collaboration with the National Health Service (NHS) to enable generation of clinical data and sample flows. Moreover, in partnership with Illumina, one of the largest Next Generation Sequencing Centres in the World was created to generate the highest fidelity and most comprehensive whole genome DNA sequence produced from patients to date with high fidelity clinical data stored in de-identified format within a multi-petabyte data infrastructure. Secondly, Peter Campbell (Hinxton, United Kingdom) from The Wellcome Trust Sanger Institute introduced The International Cancer Genome project. The main aim of it is to provide important insights into the biology of cancer through discovering the genes that are frequently mutated in tumors, and with studying the patterns of mutations seen in cancer cells. Overall, the projects explore basic scientific questions about the role that somatic mutation plays in clonal evolution, ageing and development. The first session of the conference was completed with the lecture of Eleftherios Diamandis (Toronto, Canada) on the personalised biomarkers in cancer. A slow progress in cancer biomarker discovery and general speculations of scientist, believing it is unlikely to discover new serological biomarkers characterized by high sensitivity and specificity, encouraged researchers to propose a new way of improving the landscape of cancer biomarker research. Screening new patients for a great number of previously described biomarkers with high specificity (>90%), but low sensitivity (<30%) could identify new informative markers for clinical use, important for managing individual cancer patients. Moreover, this approach may explain the reasons for increased value of some biomarkers that appear only in a small group of patients. These differences in expression are likely to be linked to specific genomic alterations, which could then be found with genomic sequencing (3). Session 2: UNMET CLINICAL NEEDS IN THE PREVENTION AND TREATMENT OF CARDIO-METABOLIC DISEASES AND CANCER – COMORBIDITIES Chairs: Georges Weryha,, Nancy, France / John Lamont, Crumlin, County Antrim, United Kingdom For the introduction to the new session, Manuel Rosa Garrido (Los Angeles, United States) shared his findings in epigenetics of cardiovascular diseases and co-morbidities. Epigenetic mechanisms control gene expression at the individual locus scale as well as at the genomic scale via the formation of long range regulatory interactions and the formation of chromosome territories. Presented case –control study on mice aimed to determine the impact of such mechanisms during the development of heart failure. Manuel Rosa Garrido proposed that global remodeling of chromatin after traverse aortic constriction and CTCF depletion drives heart failure. He concluded that heart failure involves conserved structural reprogramming of chromatin microenvironments with histone marks and DNA methylation, which play an important role in controlling expression. In his speech, Abraham Aviv (New Jersey, United States) focused in the role of telomere length (TL) in etymology of chronic diseases. He pointed out that short TL have a protective role against cancer, while the trade-off for it might be susceptibility for CVD, suggesting that TL is a common factor of these diseases. Furthermore, associations manifest at the genomic level, as p associated with short LTL are also associated with CVD and SNPs associated with long leucocyte TL are also associated with several cancers. Therefore, he concluded that TL might play a causal role in CVD and some cancers. Finally, these findings also have considerable ramifications for longevity of humans. ORAL COMMUNICATIONS SESSION Chairs: Sofia Siest, Nancy, France, Eric Boerwinkle, Houston, United States
- Said El Shamieh (Beirut, Lebanon): Genetic and protein profiling of cancer tumours, a first step towards personalised therapy.
- Gilles Lunzenfichter (Luzern, Switzerland): Welcome to a new world of Intelligent Connected Care.
- Alexia Giannoula (Barcelona, Spain): Temporal comorbidity patterns in prostate cancer disease trajectories based on semantic, phenotypic and genetic similarities.
- Laurent Becquemont (Paris, France): Investigation of novel biomarkers of drug-induced kidney injury in renal transplant recipients undergoing graft biopsy.
- Bianca van den Bosch (Maastricht, Netherlands): Evolution of dihydropyrimidine dehydrogenase (DPD) diagnostics in a single center in a time-period of eight years.
- Carlos Malpica (Doha, Qatar): Bridging the Multi-Omics Precision Medicine Gap in the Middle East: The Valdia Health Experience.
CLOSED MEETING - MAST4HEALTH PROJECT The 9th Santorini Conference started with the closed meeting, reserved for the collaborators of the MAST4HEALTH project, a Marie Sklodowska-Curie Actions (MSCA) Research and Innovation Staff Exchange (RISE) program under the EU Horizon 2020 framework. THE ODYSSEY FROM HOPE TO PRACTICE The conference was officially open with the welcome by Sofia Siest, who made a brief summary about the evolution of this colloquium in the past 16 years, initiated in 2002 and thus being the oldest International conference in the field of Personalised Medicine and Pharmacogenomics, and one of the most important conferences on genetic predisposition to health, diseases, response to drugs and environment. After 16 years, the 9th Santorini Conference “Systems Medicine and Personalised Health and Therapy” aims to reflect on the frontiers of current genomic knowledge in the fields of cardio-metabolic diseases and cancer and to reveal the practical use of this knowledge in disease prevention, diagnosis and pharmacogenomics aiming to directly impact the socio-economic aspects of public health. Sophia Siest’s presentation was inspired by the Odyssey, Greek ancient epic poem of Homer, and she embarked with the attendees on a ship from Troy-Hope to Ithaca-Practice, coursing through the history of the momentous events and achievements that paved the way for personalised medicine. She set sail amidst important genetic discoveries and obstacles that are slowing the potential full implementation of accumulated knowledge into everyday practice, beginning with the discovery of the first human genome and voyaging through the projects that contributed to the progress of personalised medicine. Following the opening words of Sofia Siest, the keynote lecture, presented by Eric Boerwinkle (Houston, United States) carried on with the journey to personalised medicine and unraveled the landmarks and challenges of the field. He discussed about the necessity of GWAS studies and their input in the discovery of new genes, but the inclusion of ethic variations is also necessary for taking the knowledge further. He pointed out that apart from genes, their interactions with environment through time should be a actively considered in genomic research. He discussed also about pharmacogenomics and the importance of including genomic information in medical guidelines. The importance of technological advances was also mentioned as a lesson learned even from Homer’s era. He concluded that Ithaca for personalised medicine should be based on relating clinicians and researchers and include improved sequencing to improve diagnostics and and personalisation of therapy of severe and chronic diseases.