Prognostic impact of somatic mutations among patients with pleural and peritoneal mesothelioma

Mesothelioma is a rare cancer with poor prognosis. Somatic mutations show prognostic value in smaller studies; however, detailed survival analysis of mutations, specific variants, and co-mutations are unknown. This study gathered one of the largest mesothelioma cohorts in North America to determine prognostic impact of treatments, tumor characteristics, and somatic mutations. Among 195 patients, 70% (n = 137) had pleural and 30% (n = 58) had peritoneal mesothelioma. NF2, TERT, and CDKN2A had worse OS in pleural mesothelioma. NF2 mutations with truncated NF2 protein (non-sense and frameshift with premature stop codon) had worse OS in pleural mesothelioma (log-rank-p < 0.001). Conversely, NF2 pathogenic mutations with loss-of-function/structural variants were not associated with OS, revealing that NF2 truncating mutations may drive NF2's prognostic impact. This is emphasized by higher mortality at 1-year (44% vs 7.7%, p = 0.044) and 18-months (69% vs 17%, p = 0.006) compared to non-truncating NF2 mutations. Overall, this study found that pleural and peritoneal mesothelioma have unique mutations with prognostic significance. Furthermore, as trials demonstrate varied results in NF2-targeted treatments, this study supports biomarker-informed strategies to guide trial enrollment and development of targeted-therapies.