Molecular Characterization of Peritoneal Mesotheliomas

Abstract

Introduction: Malignant peritoneal mesothelioma (MPeM) is clinically distinct and less studied than malignant pleural mesothelioma. We report the genomic and immunophenotypic features of a prospectively collected MPeM cohort.

Methods: Next-generation sequencing (NGS) was performed on MPeM tumors. Genomic near-haploidization (GNH) was assessed. WT1, BAP1, mesothelin, VISTA, and programmed death-ligand 1 were evaluated by immunohistochemistry (IHC) when tissue was available. Overall survival was stratified by selected genomic and IHC features.

Results: A total of 50 consented patients with MPeM (45 epithelioid, 5 nonepithelioid) were studied exhibiting common alterations in BAP1 (60%; 30 of 50), NF2 (24%; 12 of 50) SETD2 (22%; 11 of 50), and TP53 (16%; 8 of 50). A total of 76% (38 of 50) of specimens were assessable for allele-specific copy number analysis; 8% (3 of 38) had GNH. IHC positivity rates were 93% (37 of 40) for mesothelin, 96% (46 of 48) for WT1, 50% (19 of 38) for programmed death-ligand 1, and 89% (34 of 38) for VISTA. BAP1 loss by IHC was observed in 76% (29 of 38), including five wild-type on NGS. Combining NGS and IHC for BAP1, overall survival was worse with alteration or loss compared with wild-type or retained in all patients (n = 37 versus 13, 43.8 versus 117.3 mo, p = 0.04) Three of 30 patients had a pathogenic germline variant: POT1 I78T, MUTYH R109Y, and BAP1 E402∗.

Conclusions: MPeM has distinct biology and genomic composition. CDKN2A/B alterations were rare in MPeM, whereas BAP1, NF2, TP53, SETD2, and LATS2 were common. BAP1 alteration/loss was associated with shorter survival when all patients were included. A notable minority of specimens had GNH associated with NF2, TP53, and SETDB1 mutations. Pathogenic germline mutations were found in 3 of 30 patients.

Keywords: BAP1; Genomics; Malignant peritoneal mesothelioma; Next-generation sequencing.

Fig. 1.

Oncoprint of patients with peritoneal mesothelioma. The percentage of alterations by gene across all patients (n=50) is indicated to the right of the row. TMB: tumor mutation burden (mutations/megabase); FGA: Fraction Genome Altered; GNH: genomic-near haploidization.

Fig. 2:

Overall survival for patients with peritoneal mesothelioma harboring a BAP1 alteration and/or BAP1 loss by immunohistochemistry (IHC) versus wildtype/retained in A) all patients (n=50) and B) the subset with epithelioid histology (n=45). alt: altered (mutation/deletion); loss: loss of BAP1 staining on IHC; wt: wildtype; retained: retained BAP1 staining on IHC, HR: hazard ratio, CI: confidence interval.