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ESHG 2015- Day Three Summary

Scott Brouilette, Ph.D.
| Jun 09, 2015
sunny glasgow

Day three and we have a sunny Monday morning to get us going… are we still in Glasgow..? However, the high from the beautiful weather soon dissipated once we settled into the “Evolution of the Cancer Genome” session, starting with Professor Timothy Ley (Washington University). Tim’s topic was acute myeloid leukaemia (AML), a malignant, clonal disorder of the hematopoetic stem cell pool. In the United States, Tim has seen 19,000 new cases in 2014 with some 14,000 deaths, often within just a few weeks of diagnosis, and the standard-of-care is frequently a clinical trial. Interestingly, the relative global incidence of AML has remained constant over recent years, but does increase as a function of age. As we age, initiating mutations accumulate and “clonal skewing” occurs; the initiating event is often in DNMT3 followed by mutation to NPM1. Current risk classification is based on cytogenetics but is imperfect - a sequencing approach in 200 subjects showed that 23 genes are commonly mutated in AML, but knowing this did NOT improve the ability to assess risk. Tim speculated that this may be due to looking at just the exome, so they used WGS to compare short- versus long-term remission in AML, but again this failed to improve risk prediction. And so there are clearly confounding variables: mutational and clonal complexity means that 30X coverage cannot undercover the rare mutations - increasing to 300X was required. And this highlights the issue of studying a disease where there are potential multiple clones with varying numbers of cells harbouring pathogenic mutations.

Ville Mustonen (Sanger) continued this theme, but in relation to melanoma - at diagnosis, a 1cm^3 tumour may already consist of 1 billion cells with multiple clones. While initial treatment may prove successful, it is often relatively short-lived with resistance quickly developing via both existing and de novo mutations as the tumour grows, and so sampling at multiple time-points is essential to assay the diversity and size of the various clones using a tool such cloneHD. Using such an approach would mean that every tumour can be genotypically and phenotypically monitored to guide treatment as it being applied…a true example of precision medicine. 

It is often easy to overlook the many workshops that run parallel to some of the sessions, but I did spot something that sounded interesting on the agenda: “The Genetic Clinic of Future”. This consisted of a series of talks about how (and indeed why) people would want to undergo sequencing. Bogi Eliasen (Copenhagen Institute for Futures Studies ) pondered whether healthcare is a “Disease System” or a “Health System” and reiterated that to move forwards with precision medicine we need to first understand what it means to be healthy. But why would a seemingly healthy person want to be sequenced? What’s in it for them, and what are the risks? But clearly people are willing, as evidenced by the HealthSeq Project.

In the future, we are likely to see a blurring of the lines that distinguish health and disease; a continuum will exist from the super-healthy to chronic disease states. At first, the ability to get this kind of information would seem to offer the right incentives- you can potentially identify cancer-initiating mutations, and initiate appropriate therapies. But a member of the ESHG audience suggested that we may also see over-medicalisation whereby otherwise healthy people are suddenly told that actually they have a potentially pathogenic variant, in essence- a genetic “illness”. How will this affect them, particularly if there is no treatment? That is difficult to answer, but the discussion came back to the need for broader education around the role of genetics in health and disease. If engaging healthy citizens in genetic studies are a priority, they need to understand the need, the risks and the implications of the information that comes from studies.

In terms of recruiting the general public into genomics, Kassim Javaid (Oxford) introduced a relatively new way of raising interest. Referring to the Rare UK Disease of bone, joint and blood vessels, he showed how patients can arrange a call, register, then simply login to the study using a site modelled loosely on FaceBook. Participants agree how they want to be contacted, and how frequently, and they can change these preferences at any time. The team have regular patient forum discussions on Skype to ensure two-way discussions, something that has proved invaluable for making ethical amendments to the study. Traditionally, when a study makes such amendments, the timeframe for calling participants back in, discussing the changes and re-consenting them can be lengthy. In contrast, Kassim’s participants get an email, the ethics agreements are all set to “off/no”; then the participant simply logs back in and updates their settings. The web-based system has shown clear successes.

Many people are simply apprehensive about genetics and sequencing, prompting Mathieu Boudes (EURORDIS ) to use an interesting analogy: “Every one of us has a microwave oven at home. But I bet your grandparents or even your parents were scared of it at first, thinking it is too dangerous. But now they see how it benefits them in everyday life - it is just accepted." Hopefully, in time this is how sequencing individual genomes will be viewed.