| Summary: | Well-differentiated papillary mesothelioma (WDPM) is an uncommon mesothelial proliferation that is most commonly encountered as an incidental finding in the peritoneal cavity. There is controversy in the literature about whether WDPM is a neoplasm or a reactive process and, if neoplastic, whether it is a variant or precursor of epithelial malignant mesothelioma or is a different entity. Using whole exome sequencing of five WDPMs of the peritoneum, we have identified distinct mutations in <i>EHD1</i>, <i>ATM</i>, <i>FBXO10</i>, <i>SH2D2A</i>, <i>CDH5</i>, <i>MAGED1</i>, and <i>TP73</i> shared by WDPM cases but not reported in malignant mesotheliomas. Furthermore, we show that WDPM is strongly enriched with C > A transversion substitution mutations, a pattern that is also not found in malignant mesotheliomas. The WDPMs lacked the alterations involving <i>BAP1</i>, <i>SETD2</i>, <i>NF2</i>, <i>CDKN2A/B</i>, <i>LASTS1/2</i>, <i>PBRM1</i>, and <i>SMARCC1</i> that are frequently found in malignant mesotheliomas. We conclude that WDPMs are neoplasms that are genetically distinct from malignant mesotheliomas and, based on observed mutations, do not appear to be precursors of malignant mesotheliomas.
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