Molecular Characterization of Mesothelioma: Impact of Histologic Type and Site of Origin on Molecular Landscape.

Abstract

Mesothelioma is an aggressive malignancy with heterogeneous outcomes that are partly driven by the differential efficacy of existing therapies across histologic types and sites of origin. Large-scale molecular analysis of mesothelioma and its subtypes has the potential to inform future therapeutic strategies. We analyzed 1,294 mesotheliomas {980 pleural (malignant pleural mesothelioma [MPM]) and 314 peritoneal (malignant peritoneal mesothelioma [MPeM])} using next-generation sequencing, determined programmed death ligand-1 (PD-L1) expression and histology in a subset of cases, and assessed <i>MTAP</i><i>/CDKN2A</i> copy-number status by fluorescence in situ hybridization and T-cell infiltration in an independent cohort. The molecular landscape of MPM was characterized by inactivating alterations in <i>CDKN2A</i> (49%), <i>BAP1</i> (44%), <i>CDKN2B</i> (42%), <i>MTAP</i> (34%), and <i>NF2</i> (33%). Compared with epithelioid MPM, nonepithelioid (ie, biphasic and sarcomatoid) MPM had identical tumor mutational burden (median 1.25 mut/Mb, <i>P</i> = .63), more commonly expressed PD-L1 (74% <i>v</i> 51%, <i>P</i> = .02), and was more likely to harbor <i>MTAP</i>, <i>CDKN2A</i>, and <i>CDKN2B</i> copy loss (<i>P</i> < .05). Fluorescence in situ hybridization confirmed that homozygous <i>MTAP</i> loss was enriched in nonepithelioid MPM. Relative to MPM, MPeM had comparable tumor mutational burden and PD-L1 expression. The molecular profile of MPeM was similar to MPM, with the distinction that <i>PBRM1</i> alterations occurred at higher frequency (16% <i>v</i> 7%, <i>P</i> < .01). <i>ALK</i> rearrangements were only observed in MPeM. Regardless of histology and location, the molecular landscape of mesothelioma primarily consists of inactivating alterations in tumor suppressor genes, with enrichment of certain alterations in distinct subsets (eg, <i>MTAP</i> loss in nonepithelioid tumors). Given the limited efficacy of current therapies for this disease, novel approaches targeting recurring alterations should be explored.