Swiss Re R isk Dialogue Series Risk Dialogue Series Genomic medicine Genomic medicine Editorial Recent decades have seen massive advancements in genomic medicine. This has resulted in establishing a wealth of disease associations with genetic variances in the genome. At the same time, the extensive use of genome analysis tools has resulted in a massive decrease in the cost of genome sequencing. Today, genetic testing companies are offering full genome sequencing for below USD 1000. The growing availability and utility of genetic information is becoming an increasingly important aspect of modern personalised medicine, due to the ability to deliver patient-tailored health care based on an individual’s genetic makeup. The emerging field of epigenetics, studying dynamically evolving changes in gene expression in response to environmental stresses, has added an additional layer of complexity to our understanding of the genome. As with genomic studies, current epigenetic research is rapidly evolving into potential clinical applications. The latest advances in genetic science will improve disease diagnosis and aid in guiding and applying personalised treatment and prevention plans. These advances include liquid biopsy, which identifies cancer cells or DNA in bodily fluids, requiring minimally invasive extraction; and the development of CRISPR technology, which allows precise and efficient gene editing in any organism. These new tools and techniques, combined with the growing availability of genomic information and new predictive methodologies, are entering clinical practice. They will challenge how we as insurers define disease; how we structure and price our policies; and how we sustainably provide our products and services to our customers. We wish you an enjoyable read. Edouard Schmid Christoph Nabholz Group Chief Underwriting Officer Head R&D Life & Health Swiss Re Swiss Re Swiss Re Risk Dialogue Series: Genomic medicine 1 Contents Preface 1 Edouard Schmid, Group Chief Underwriting Officer, Swiss Re Christoph Nabholz, Head R&D Life & Health, Swiss Re Introduction 5 Christoph Nabholz, Head R&D Life & Health, Swiss Re Florian Rechfeld, Senior Research Analyst L&H, Swiss Re Genomic medicine in clinical practice 9 Vincent Mooser, Professor of Medicine and head of the Lab Department at Lausanne, CHUV University Hospital Jacques Fellay, Head of the Precision Medicine Unit at the CHUV University Hospital in Lausanne Transgenerational epigenetic inheritance: A paradigm shift in biology and medicine 21 Johannes Bohacek, Group leader in the Mansuy lab at the Brain Research Institute of the University of Zurich Isabelle M Mansuy, Professor in Neuroepigenetics at the Medical Faculty of the University of Zurich Liquid biopsy in oncology 31 Nicola Aceto, Professor of Oncology and Group Leader of the Cancer Metastasis laboratory at the University of Basel Liquid biopsy – a new blood test for cancer challenges the insurance industry 41 Giselle Abangma, Health Research Analyst, Swiss Re Christoph Nabholz, Head R&D Life & Health, Swiss Re Florian Rechfeld, Senior Research Analyst L&H, Swiss Re John Schoonbee, Global Chief Medical Officer, Swiss Re Future clinical applications of gene editing in humans 49 Thomas Wildhaber, Analyst, Swiss Re Christoph Nabholz, Head R&D Life & Health, Swiss Re Séverine Rion Logean, Head Life & Health R&D Europe, Swiss Re Swiss Re Risk Dialogue Series: Genomic medicine 3 Introduction Genomic medicine is an emerging branch of medicine that involves an individual’s unique genetic makeup to customise medical care. The present form of genomic medicine is a direct result of the human genome sequencing project which started in 1990 aiming to identify and map all of the human genes. Thirteen years and USD 3 billion later, the project had successfully sequenced the human genome. The year 2007 marked another turning point with the application of next generation- sequencing (NGS) technology to uncover the roles of rare individual genetic variances in common diseases. The cost of genome sequencing subsequently plummeted and currently stands at around USD 1000 (Figure 1). These technological advances have led to a major leap forward in the scope of genomics and its growing role in the delivery of healthcare. $ 100M $ 10M Moore’s Law $ 1M $ 100K $ 10K $ 1K 11 12 13 14 15 10 07 01 02 03 09 08 05 06 04 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 Source: National Human Genome Research Institute https://www.genome.gov/sequencingcostsdata/ Figure 1: Cost per genome Genomic medicine in clinical practice Individual genetic information will play an In the first article of this collection, Vincent Mooser, Professor of Medicine and increasingly important role in healthcare. Jaques Fellay, Head of the Precision Medicine Unit, both located at Lausanne CHUV University Hospital, explore genomic medicine in clinical practice. The authors conclude that the use of individual genetic information plays a key role in modern medicine and will fundamentally change the way we predict, prevent, diagnose and treat diseases in the near future. Genetic tests will become particularly Genetic testing will become a cornerstone of cancer diagnosis, allowing physicians important in identifying and treating to identify and classify tumours based on their genetic signatures in addition to their cancer and other serious diseases. location in the body. Furthermore, results from genetic testing can be useful to evaluate the prognosis of an individual’s cancer and to cross-reference the results to known treatment options for a patient’s particular mutations. Expectations are high that genetic testing will accurately predict the risk for various diseases and eventually lead to preventive and therapeutic interventions that are targeted to at-risk individuals based on their genetic profiles. Creating Genetic Risk scores could aid Latest research has led to the development of Genetic Risk Scores (GRS) combining insurance underwriting … individual genetic variants associated with a specific disease. Such risk scores enable stratification of individuals into low- and high-risk groups for common disorders such as heart disease, diabetes and most cancers. Swiss Re Risk Dialogue Series: Genomic medicine 5 Introduction In terms of insurance, GRS for breast cancer, for example, have been shown to have a better risk prediction than a score based on non-genetic risk factors (BMI, smoking status, alcohol, and family history of breast cancer) routinely assessed in insurance underwriting. Even better predictions can, however, be achieved using a combination of genetic and non-genetic factors. Along with traditional risk factors used in insurance underwriting, reliable GRS may become an additional or alternative technique for risk stratification of insurance applicants. … however, insurers are restricted in their Insurers are supportive of the many advantages clinically relevant genetic testing has use of genetic tests. to offer in the prediction, prevention, diagnosis and treatment of disease, thereby increasing life expectancy or decreasing morbidity. It is currently common insurance best practice that applicants are not requested to undertake any genetic tests as part of the application procedure. Insurers are in turn wary of information However, insurers are also concerned that individuals may not share existing reliable asymmetries based on genetic tests. and risk-relevant genetic information from predictive genetic testing with them, thereby increasing insurers’ exposure to adverse-selection. The effects of adverse- selection are accentuated by ongoing legislative and regulatory processes in a number of countries restricting the request and use of genetic tests for underwriting purposes. Recent studies have shown that the financial impact of non-disclosure and/or restriction in access and use of existing predictive genetic information could be substantial to insurers. As a consequence, insurers may re-consider their underwriting, product design and pricing practices. Preserving the symmetry of information between insurers and applicants will be vital for the efficient operation of insurance markets. Transgenerational epigenetic inheritance: A paradigm shift in biology and medicine Epigenetics may prove as significant to The contribution of Professor Isabelle Mansuy and Dr. Johannes Bohacek from the health as the underlying genetic fingerprint. University of Zurich discusses the topic of epigenetics – the study of heritable changes in gene expression, which serve as an additional layer on top of genetics. Different epigenetic mechanisms have been shown to regulate the temporal and spatial control of genes, without changing the underlying genetic code. Such epigenetics changes can be inherited by future generations, although the detailed molecular mechanism of this inheritance are not fully understood. Notably, these mechanisms are responsive to environmental factors and play a fundamental role in the development and in health and disease. Geneticists believe that epigenetic alterations are as important as genetic mutations for the initiation and progression of progressive diseases such as cancer or diabetes. The increased understanding of epigenetic imprint mechanisms in disease manifestation holds great promise for developing prevention, detection, and therapy approaches. Epigenetics are further a good proxy for Furthermore, epigenetic modifications have been used to develop an “epigenetic general health status, and are being used clock” to estimate the biological age