Comparative Gene Expression Analysis of Epithelioid Pleural and Peritoneal Mesothelioma

Background/Objectives: Pleural and peritoneal mesothelioma (PL and PE) are aggressive diseases, accounting for 68.0–92.4% and 6.9–24.1% of all cases. To improve both diagnosis and management of these patients, a deeper knowledge and characterization of the molecular background are necessary. Although molecular profiling of PL has been largely investigated in recent years, much less is known about the genomic landscape of PE, due to its rarity. Here, we aim to compare gene expression profiling of pleural and peritoneal mesothelioma to underline main differences and to identify new potential histotype-specific biomarkers. Methods: We performed a gene expression analysis of 32 epithelioid PL and 21 epithelioid PE cases, diagnosed from 2017 to 2023 at the University Hospital of Pisa, using an nCounter custom panel including 117 target genes known for their crucial role in cancer. Results: PE, compared to PL, showed different expression levels of genes related to extracellular matrix modification (ECM), as collagen alteration, pro-inflammatory and angiogenic response (mediated by NF-κB). In detail, in PE we observed a significant upregulation of metalloproteinase-1 (MMP1), E-selectin (SELE), pappalysin-1 (PAPPA), estrogen receptor-2 (ESR2) and transportin-2 (TNPO2); and a downregulation of pyruvate kinase (PKM). Furthermore, BAP1 loss was associated with distinct gene deregulation in PE and PL; the only exception was ASS1 upregulation, which was observed in both histologies. These insights may help refine the utility of BAP1 as a biomarker. Conclusions: Deregulated genes in PE deserve further investigation as potential biomarkers, according to their biological role. In fact, MMPs and PAPPA impact migration ability and angiogenic response of mesothelioma, while PKM and ESR2 are usually investigated for their involvement in reprogramming of energy metabolism. The identification of histotype-specific biomarkers is warranted to improve mesothelioma management.