Inferring the evolutionary history of premalignant mesothelioma to identify drugable bottlenecks for therapy and prevention

Open to UK applicants only

Supervisor:

• Professor Dean Fennell

Project:

Background, rationale and aims
Mesothelioma is a rare cancer that uniquely, is caused by exposure to asbestos. It is an incurable malignancy associated with a survival time of 18 months. The UK has the highest incidence in the world, with the rate increasing in females. Mesotheliomas take around 30 years to form following exposure to asbestos, however the stepwise evolutionary pathway that leads to an established mesothelioma is poorly understood. Uncovering the natural history of asbestos induced mesothelioma prior to diagnosis should reveal critical evolutionary bottlenecks that could serve as targets for precision drug therapy, screening and potentially biomarkers to spearhead preventative interventions. 
Leicester has pioneered the study of mesothelioma evolution reporting early pilot data , and the aim of this project is to leverage our unique cohort comprising multi-omic and clinical data to definitively decipher, at scale, the premalignant stepwise mutations that lead to mesothelioma RESEARCH PLAN
1. The stepwise evolution of mesothelioma
The research fellow will undertake phylogenetic analysis applying a probabilistic framework (PhylogicNDT) to existing whole exome sequencing data from 9 leicester-led mesothelioma cohorts (MEDUSA1, CONFIRM2, VIM3, NERO4, MIST15, MIST26, MIST3 7, MIST4 8, and MIST5 9) collectively comprising over 900 patients. The aim will be to definitely identify the temporal ordering of somatic copy number and single nucleotide variations occuring during mesothelioma evolution. Using parallel whole genome data the timing of these events will be inferred. Patterns of evolution will be inferred through transfer learning and clustering of similar trajectories and their phenotypic correlations established.  Mutation processes and phenotype will be correlated with evolutionary trajectory clusters. 

2. Elucidating the causes of mutation induced by asbestos. 
It is currently not known how asbestos induces mutations during mesothelioma transformation. Early findings from our team suggest that endogenous retrovirus induced mutagenesis (L1 retrotransposition) may connect asbestos induced inflammation to genomic alterations. This project will allow, at scale interrogation of key driver copy number alterations to determine whether there is significant association between ERV mediated DNA breakage and initiation of mesothelioma.

IMPACT AND IMPLICATIONS OF THIS RESEARCH
This PhD proposal will provide rigorous training in translational bioinformatics techniques linked to cancer phylogenetic analysis. It is envisaged that this project will uncover for the first time, how asbestos transforms normal mesothelium ie. the temporal ordering of genomic changes, and the underlying causes. This information will be used to identify critical bottlenecks to priorise for stratified therapy, and that could to enable future screening and prevention of mesothelioma