HGV2014 Meeting Report, Session 5 “IMPROVING OUR HEALTH: TIME TO GET PERSONAL”
Caveats: I have not taken notes in every talk of every session, a lack of notes for a particular speaker does not constitute disinterest on my part, I simply took notes for the talks that were directly related to my current work. If I have misquoted, misrepresented or misunderstood anything, and you are the speaker concerned, or a member of the team involved in the work, please leave a comment on the post, and I will rectify the situation accordingly.
5.1 Mark Lawler, QUB, Belfast: “Personalised Cancer Medicine; Are we there yet?”
Another talk from Mark who was an excellent chair for some conference sessions as well. One of the biggest problems with personalized medicine is that some data is already silo’d, or at very best fragmented.
In the UK getting science into clinical practice within the NHS is really predicated on the evidence that it reduces costs, is transformational in terms of treatment and adds value to the current system. So the bar is set quite high.
This was contrasted with the INCa Tumour Molecular Profiling Programme which is running in France with colorectal and lung cancers. This is drawing on 28 labs around Europe. INCa appears to be run under the auspices of the Institut National du Cancer.
Critical resource: http://www.e-cancer.fr/en
Mark felt that empowering patient advocacy was going to be an important drive in NHS uptake of new technologies and tests. But equally important was increasing personalized medicine literacy amongst GPs, policymakers and the insurance industry.
5.2 Nazneen Rahman, ICR, London “Implementing large-scale, high-throughput cancer predisposition genomic testing in the clinic”
Nazneen is obviously interested in testing germline mutations unlike much of the rest of the cancer programme which was focused on somatic mutation detection. Consequently working with blood draws and not biopsy material.
There are >100 predisposition genes implicated in 40+ cancers and there is variable contribution depending on the mutation and the cancer type. 15% of ovarian cancers result from germline variants, and this falls to 2-3% of all cancers. For this kind of screening a negative result is just as important as a positive one.
On the NHS testing for about half these predisposition genes is already available but even basic BRAF testing is not rolled out completely so tests have ‘restricted access’.
What is really needed is more samples. Increased sample throughput drives ‘mainstreaming of cancer genetics’. And three phases need to be tested – data generation, data analysis and data interpretation.
Critical resource: http://mcgprogramme.com/
They are using a targeted panel (CAPPA – which I believe is a TruSight Cancer Panel) where every base must be covered to at least 50x, which means mean target coverage of samples approaches 1000x even for germline detection. There’s a requirement for a <8week TAT and positive and negative calls must be made. It was acknowledged that there will be a switch to WEX/WES ‘in time’ when it is cheap.
The lab runs rapid runs on a HiSeq 2500 at a density of 48 samples per run. This gives a capacity of 500+ samples per week (so I assume there’s more than one 2500 available!). 50ng of starting DNA is required and there is a very low failure rate. 2.5k samples have been run to date. 384 of these were for BRCA1/2. 3 samples have failed and 15 required ‘Sanger filling’.
In terms of analysis Stampy is used for the aligner and Platypus for variant calling due to its superior handling of indels. A modified version of ExomeDepth is used for CNV calling and internal development produced coverage evaluation and HGVS parsers. All pathogenic mutations are still validated with Sanger or another validation method.
Data interpretation is the bottleneck now, its intensive work for pathogenic variants, and VOUS are an issue – they cannot be analysed in a context independent fashion and are ‘guilty until proven innnocent’ in the clinicians mind.
They have also performed exome sequencing of 1k samples, and observed an average of 117 variants per individual of clinical significance to cancer and 16% of the population has a rare BRCA variant.
Nazneen prefers to assume that VOUS are not implicated in advance, we should stick to reporting what is known, until such time a previous VOUS is declared to be pathogenic in some form. But we should be able to autoclassify 95% of the obvious variants, reducing some of the interpretation burden. Any interpretation pipeline needs to be dynamic and iteratively improved with decision trees built into the software. As such control variant data is important, ethnic variation is a common trigger for VOUS, where the variant is not in the reference sequence, but is a population level variant for an ethnic group.
Incorporating gene level information is desirable but rarely used. For instance information about how variable a gene is would be useful in assessing whether something was likely to be pathogenic – against a background which may be highly changeable vs. one that changes little.
Although variants are generally stratified into 5 levels of significance they really need to be collapsed down into a binary state of ‘do something’ or ‘do nothing’. A number of programs help in the classification including SIFT, PolyPhen, MAPP, AlignGVD, NN-Splice, MutationTaster. The report also has Google Scholar link outs (considered to be easier to query sanely than PubMed).
To speed analysis all the tools are used to precompute scores for every base substitution possible in the panel design.
5.3 Timothy Caulfield, University of Alberta, Canada: “Marketing the Myth of Personalised Prevention in the Age of Genomics”
No notes, here but an honorable mention for Tim who gave what was easily the most entertaining talk of the conference focusing on the misappropriation of genomics health by the snake oil industries of genomic matched dating, genomic influenced exercise regimes and variant led diets. He also asked the dangerous question that if you 1) eat healthily 2) don’t smoke 3) drink in moderation 4) exercise is there really any value in personalized medicine except for a few edge cases? Health advice hasn’t changed much in decades. And people still live unhealthily. You won’t change this by offering them a genetic test and asking them to modify their behavior. If you ever have a chance to see Tim speak, it’s worth attending. He asked for a show of hands who had done 23andMe. Quite shocking for a genetics conference 3 people had their hand in the air. Myself, Tim and one of the other speakers.