Abstract
Malignant Pleural Mesothelioma (MPM) is typically diagnosed 20–50 years after exposure to asbestos and evolves along an unknown evolutionary trajectory. To elucidate this path, we conducted multi-regional exome sequencing of 90 tumour samples from 22 MPMs acquired at surgery. Here we show that exomic intratumour heterogeneity varies widely across the cohort. Phylogenetic tree topology ranges from linear to highly branched, reflecting a steep gradient of genomic instability. Using transfer learning, we detect repeated evolution, resolving 5 clusters that are prognostic, with temporally ordered clonal drivers. BAP1/−3p21 and FBXW7/-chr4 events are always early clonal. In contrast, NF2/−22q events, leading to Hippo pathway inactivation are predominantly late clonal, positively selected, and when subclonal, exhibit parallel evolution indicating an evolutionary constraint. Very late somatic alteration of NF2/22q occurred in one patient 12 years after surgery. Clonal architecture and evolutionary clusters dictate MPM inflammation and immune evasion. These results reveal potentially drugable evolutionary bottlenecking in MPM, and an impact of clonal architecture on shaping the immune landscape, with potential to dictate the clinical response to immune checkpoint inhibition.
Highlights
Malignant Pleural Mesothelioma (MPM) is typically diagnosed 20–50 years after exposure to asbestos and evolves along an unknown evolutionary trajectory
Major questions remain regarding the extent and clinical significance of genomic intratumour heterogeneity (ITH) in MPM, and in particular whether constrained, temporal ordering of driver events is required for MPM transformation; critical information that could help to inform the development of precision therapy[5,11]
We conducted multi-regional whole-exome sequencing of 90 tumour regions from 22 patients undergoing routine surgery by extended pleurectomy decortication
Summary
Malignant Pleural Mesothelioma (MPM) is typically diagnosed 20–50 years after exposure to asbestos and evolves along an unknown evolutionary trajectory. Major questions remain regarding the extent and clinical significance of genomic intratumour heterogeneity (ITH) in MPM, and in particular whether constrained, temporal ordering of driver events is required for MPM transformation; critical information that could help to inform the development of precision therapy[5,11]. Clinical phylogenetic studies such as TRACERx lung[12] have shown that clonal neoantigen architecture drives immune surveillance[13] which in turn is a selection pressure leading to immune evasion via immunoediting[14,15]. We show that clonal architecture in MPM affects patient survival and composition of the tumour microenvironment
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