Pervasive chromothripsis drives pleural mesothelioma to impact gene function and patient survival

Pleural mesothelioma (PM) is a tumour type showing high structural complexity but the full spectrum of variants present and their impacts are poorly understood. We comprehensively describe the mutational landscape of mesothelioma, exploiting a large (N=443) cohort profiling the tumour genome and transcriptome in parallel. We find that the majority of candidate driver variants are mediated by copy number alterations (CNAs) and discover high frequencies of complex rearrangements across most tumours, dominated by chromothripsis (74% of tumours) and chromoplexy (59%). Chromothripsis contributes to significant CNA hotspots to delete known PM tumour suppressor genes such as CDKN2A, NF2 and BAP1, thought to be among the earliest events in PM development; and the presence of chromothripsis is associated with significantly worse patient survival. We also discover multi-faceted crosstalk between the mitochondrial and nuclear genomes during PM evolution, involving alterations to both genomes, and mitochondrial expression changes associated with subtypes and chromothripsis.