Interrogating inter- and intratumour genomic heterogeneity in mesothelioma

BackgroundDespite recent advances, treatment options for patients with malignant pleural mesothelioma (MPM) are limited and prognosis remains poor. The aims of this work were to better understand the somatic copy number alteration (SCNA) landscape of MPM and to identify potential therapeutic targets, to determine genetic factors predicting outcome following radical surgery, and to develop an evolutionary study of MPM.MethodsThe Affymetrix Oncoscan array was used to evaluate SCNAs from 94 tumour samples. Common SCNAs were evaluated as potential therapeutic targets, including PRMT5 as a synthetic lethal target for MTAP in vitro. SCNA profiles of patients with extremes of outcome following radical surgery were compared to determine any genetic predictors of outcome. A second set of tumours was analysed in an attempt to validate these findings. A pilot of the Medusa study (NCT03654833) was carried out to evaluate the genomic spatial heterogeneity within 6 MPM tumours by whole exome sequencing.ResultsDeletion of 9p21.3 was the most prevalent SCNA. MTAP was shown to have potentially synthetic lethal interaction with PRMT5 in vitro. Deletion of CDKN2A was a truncal event in 67% of cases. BAP1 and NF2 were commonly heterozygously deleted, with mutation of the remaining allele a truncal event on phylogenetic analysis. A group of 47 SCNAs were exclusive to patients with a short time to progression, and having one or more of these predicted outcome.Conclusions Several potential therapeutic targets have been identified. The presence of one or more specific SCNAs could give a measure of prognosis for patients from routinely obtained tumour tissue samples.