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

Abstract

PURPOSE 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. MATERIALS AND METHODS 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 MTAP /CDKN2A copy-number status by fluorescence in situ hybridization and T-cell infiltration in an independent cohort. RESULTS The molecular landscape of MPM was characterized by inactivating alterations in CDKN2A (49%), BAP1 (44%), CDKN2B (42%), MTAP (34%), and NF2 (33%). Compared with epithelioid MPM, nonepithelioid (ie, biphasic and sarcomatoid) MPM had identical tumor mutational burden (median 1.25 mut/Mb, P = .63), more commonly expressed PD-L1 (74% v 51%, P = .02), and was more likely to harbor MTAP, CDKN2A, and CDKN2B copy loss ( P < .05). Fluorescence in situ hybridization confirmed that homozygous MTAP 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 PBRM1 alterations occurred at higher frequency (16% v 7%, P < .01). ALK rearrangements were only observed in MPeM. CONCLUSION 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, MTAP loss in nonepithelioid tumors). Given the limited efficacy of current therapies for this disease, novel approaches targeting recurring alterations should be explored.

NR4A3 fusions characterize a distinctive peritoneal mesothelial neoplasm of uncertain biological potential with pure adenomatoid/microcystic morphology

“…In one large series ( n = 1294 cases), sarcomatoid and biphasic tumors showed more frequent copy losses of MTAP , CDKN2A , and CDKN2B , compared to purely epithelioid pleural mesotheliomas 27 . Moreover, PBRM1 alterations were more frequently detected in peritoneal (16%) compared to pleural (7%) tumors 27 . Notably, ALK rearrangements were restricted to peritoneal tumors in the same study.…”

“…Herein, we expand the spectrum of gene fusions in peritoneal mesothelial neoplasms, highlighting a striking phenotype–genotype correlation that has not been previously described with the detection of an NR4A3 fusion in five of seven mesothelial tumors with prominent adenomatoid/microcystic morphology. The prevalence of NR4A3 ‐rearranged mesothelial neoplasms is likely very low; a large genetic study comprising 980 pleural and 314 peritoneal mesotheliomas did not find a single case with an NR4A3 gene fusion, 27 —the NGS panels utilized at that time covers EWSR1 and other common fusion genes but not NR4A3 —if an EWSR1::NR4A3 fusion was present, it would have been detected.…”

Complexity of progranulin mechanisms of action in mesothelioma

“…Mesothelioma is a rare aggressive malignancy with limited therapeutic options and the response to currently available therapies is highly dependent on tumor histologic subtype [ 7 ]. Progranulin is a pleiotropic growth factor playing a critical role in cell proliferation, angiogenesis, and development [ 34 , 52 ].…”

“…There are three major histologic subtypes of MM, epithelioid, biphasic and sarcomatoid with different prognosis [ 6 ]. However, a more detailed subclassification and histologic/cytological characterization of MM might have prognostic and perhaps predictive value for MM [ 6 , 7 ]. In spite of considerable work done in recent years to develop immunotherapies and biomarker-driven therapy to improve patient outcomes, there is still an unmet need for the identification of novel targets to improve therapy.…”

The Genes–Stemness–Secretome Interplay in Malignant Pleural Mesothelioma: Molecular Dynamics and Clinical Hints

“…The incidence in Europe is expected to peak around 2025 due to the long latency that can elapse between exposure to asbestos fibers and the onset of the disease [ 4 ]. MPM diagnosis is generally reached through conventional morphology and immunohistochemistry (IHC) [ 5 , 6 , 7 , 8 ]. The expressions of BAP1, EZH2, and MTAP proteins are used to classify chronic pleuritis from a malignant disease [ 9 ].…”