Development of a 6-gene mesothelioma-specific prognostic signature using whole transcriptomic analysis of mouse and human tumors

Background: Mesothelioma is an aggressive, fatal cancer that is inextricably linked to asbestos exposure. Recent trials using a combination of the immune checkpoint inhibitors ipilimumab and nivolumab has significantly improved treatment outcomes, however durable treatment responses remain restricted to a subset of patients (15-20%), highlighting the need to identify strategies that better predict treatment response. Method: Here, we performed RNAseq on a large tumor biobank from genetically diverse mouse model, CC-MexTAg model to compare gene expression profiles of tumors from mice with different overall survival to develop a prognostic gene signature. Results: while the variation in gene expression data of tumors did not associate with 3-fold variation in overall survival of CC-MexTAg mice, we identified two distinct tumor clusters characterized with immune and non-immune phenotypes, in which immune cluster tumours showed the better potential of response to cancer therapies. We used 20 hub genes associated with these tumor phenotypes to develop a 6-gene signature that could predict survival in four independent mesothelioma datasets and showed a potential to respond to cancer immunotherapy. Overall design: 167 asbestos induced tumours harvested from 119 mice, representing 35 CC-MexTAg strains.