Precision Medicine DTP - Assessing the penetrance of genes that contribute to cancer in a large population-based cohort and implementation in a clinical genetics setting

Background
Public databases of medically-ascertained genetic variation hold tens of thousands of genetic variants. For instance, ClinVar contains around 9,000 genetic variants linked to some type of cancer. However, determining the medical relevance of these variants pose a considerable challenge, and without a clear understanding of whether a variant has medical significance it is difficult to inform the clinical management of the patients and their families.

Until recently, large-scale population cohorts that benefit from both sequencing and good health records linkage were lacking. The available studies fell within one of two broad categories: (1) Well characterised cohorts with linked health data but for which genetic variation had been assayed using microarrays, like UK Biobank; (2) large cohorts with good quality sequence data but which lacked clinical information, like EXAC. This has, however, started to change. UK Biobank has just released 200,000 Whole Exome Sequencing (WES) data.

These new UK Biobank data will allow us to investigate the likely relevance for cancer of rare variants currently available in public databases. Cancer is a major contributor to morbidity and mortality in the UK, and this proposal could be transformational in the way we interpret these variants and how we action them. As the participants are linked to the UK National Cancer Registries, the data available for the study are exceptional, not only in scale, but importantly in the quality and coverage of the health records available. UK Biobank updates the cancer data roughly once a year, and they receive the data with roughly a six months delay. We will update the website estimates annually and version each new release of the estimates to allow the user to consult the most current estimates, but also past estimates. Updates will be advertised through the web portal and through a mailing list where users could join if they wished.

Aims
The overarching aim of this proposal is to systematically assess the penetrance of genetic variants linked to cancer risk in a richly-phenotyped population-based cohort of 500,000 participants with Whole Exome Sequencing (WES) data (the UK Biobank). To do that, we will:

Extract genetic variants associated with cancer from public databases that hold medically assayed human genetic variation.
Estimate risk and penetrance, i.e. the probability that a carrier of a mutation has cancer by a given age, for each of these variants and each cancer site in UK Biobank.
Test whether the combined effect of common susceptibility variants modify the cancer risk and penetrance of rare pathogenic variants in UK Biobank.
Develop a web-interface where the user can query and download our prevalence estimates in a flexible and easy way. For instance, by tumour site, organ, gene or genetic variant. The website will include a penetrance predictor for polygenetic risk scores of common variants.

Training outcomes
Profound understanding of cancer genetics.
Deep understanding of statistical techniques.
High proficiency in bioinformatic tools.
Managing big data.
Expert understanding of the clinical need for estimates of cancer risk for personalised management.
Communication of cancer risk to patients and family.
Writing and communicating science to scientist and lay public.

This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow.

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the link above.

For more information about Precision Medicine visit:
http://www.ed.ac.uk/usher/precision-medicine