ES17.01 Mesothelioma Evolution

Abstract

Malignant pleural mesothelioma (MPM) is mostly caused by prior exposure to asbestos fibres. It has a long but variable latency period following exposure, with a median of around 40 years but a range between 20-70 years, possibly reflecting the length and level of asbestos exposure as well as other environmental and genetic causes. Upon diagnosis, there are limited treatment options, and median survival time is a year, although, again, this is highly variable. Understanding the genetic events in the mesothelium between asbestos exposure and diagnosis of MPM is important for two reasons. Firstly, it will inform the biology of MPM tumour growth and potentially highlight different environmental and genetic factors that cause the variation in latency. Secondly, it will help identify key early driver mutations in MPM informing biology and candidate changes for developing approaches for early detection of the cancer. Evolutionary genetics is based on inferring past events from current genetic/genomic sequences. It has long been recognised that the development of cancer is an evolutionary process, and the availability of large amounts of DNA sequence data have facilitated an understanding of evolution of tumours using methods mostly borrowed from evolutionary genetics. One powerful approach compares a matched tumour and normal genome, infers the somatic mutations in the tumour, and uses the ratio of mutations that change an amino acid to mutations that don’t change an amino acid (dN/dS ratio) across all genes to identify particular genes that have been positively selected during tumour evolution. This approach can also shed light on overall evolutionary processes that have occurred in the tumour. Genomic sequences from multiple regions of the same tumour not only emphasise the molecular heterogeneity of tumours but allow an explicit phylogenetic tree of the evolution of the tumour for each patient, distinguishing somatic mutations that happened early in the tumour's evolution (and are therefore present throughout the tumour) from those that happened late in the tumour evolution. Here, I report preliminary findings from a British Lung Foundation/Mesothelioma UK-funded project entitled MEDUSA – Mesothelioma Evolution: Deciphering drUgable Somatic Alterations as potential targets for synthetic lethal therapy. This project uses multiregional sampling of MPMs, together with matched whole blood, to infer a phylogenetic tree of MPMs. The preliminary data presented focuses on the first 20 patients, with between 4 and 5 regions of the tumour analysed per patient. Using whole exome sequencing, the project aims to identify truncal changes, that is, mutations that happened early in the tumour and are present throughout the tumour that can be potential targets for drugs, with the aim of developing personalised, effective tumour treatment for each patient. We focus on copy number changes (deletions and duplications of genes) and confirm that MPM is highly heterogeneous with extensive copy number changes in the genome. We focus on truncal copy number changes in ∼20-25% of patients affecting the known mesothelioma tumour suppressor genes BAP1, MTOR, CDKN2A and SETD1. Distinguishing patients that have truncal copy number changes in these genes, in contrast to those patients with copy number changes in the terminal branches of the evolution of the tumour, helps to tailor individualised drug therapies. Our approach emphasises the importance of multiregional sampling of tumours to account for MPM heterogeneity. For example, by sampling the posterior costophenic angle of these MPM from these 20 patients, we would find 10 deletions of CDKN2A, of which only 5 are truncal, with the other five localised to only part of the tumour. Multiregional genomic analysis and evolutionary genetics approaches can illuminate the history of a tumour and have the potential to guide therapy. They also provide the framework for follow-on studies in a patient, such as analysing the origin of metastases and identifying the effects on the tumour of treatment. The extra information provided by multiregional sampling supports the idea that this approach should become routine in tailoring the treatment to the tumour in MPM. evolution, Mesothelioma, Genomics