Malignant pleural mesothelioma (MPM) is an incurable and aggressive cancer that occurs on pleural membranes covering the lungs and is associated with exposure to asbestos fibres. There are >15,000 cases per annum worldwide. Regulation against asbestos has slowed the increase rate of Australian deaths however for some Asian countries, continued unregulated use of asbestos means that their disease burden is set to increase. Combinations of surgery, chemotherapy and radiotherapy all feature in the clinical management but the overall survival remains at 9-24 months. Therefore new therapeutic approaches are needed.
We are assembling the world’s largest MPM whole genome sequencing resource, comprising sequencing for 54 patients with accompanying methylation and transcriptome sequencing where possible. Our results have confirmed driver gene mutations for CDKN2A, BAP1, NF2, SETD2 and TP53. For CDKN2A, BAP1 and NF2 the mutation spectrum commonly includes disruption by deletion and rearrangements breakpoints, indels and/or truncating point mutations.
Intra-tumoral heterogeneity can affect response to all types of treatment and may be identified from the whole genome sequencing. We have multiple samples from 5 MPM patients that allow us to explore inter sample evolutionary changes and relate these to the clinical course of treatment. MPM samples often have a low number of branch mutations and temporally separated samples appear largely stable.
Immunotherapy is an emerging cancer therapeutic approach with some exceptional responses in metastatic, recurrent and heavily mutated cancers. MPM cancers generally have a low mutation burden, in our cohort it is only 1.23 mutations per mega base, however recent clinical trials suggest that MPM patients may respond to immunotherapy. We have employed genomic HLA typing, neoantigen prediction and immune environment profiling to characterise the immune setting for MPM patients. Our project will characterise and integrate genomics, immune environment and clinical data to identify the underlying genomic mechanisms for therapeutic success.