Well-differentiated papillary mesothelioma of the peritoneum is genetically defined by mutually exclusive mutations in TRAF7 and CDC42

Abstract

Well-differentiated papillary mesothelioma is an uncommon mesothelial neoplasm that most frequently arises in the peritoneal cavity of women of reproductive age. Whereas malignant mesothelioma is an aggressive tumor associated with poor outcome, well-differentiated papillary mesothelioma typically exhibits indolent behavior. However, histologically differentiating between these two entities can be challenging, necessitating the development of distinguishing biomarkers. While the genetic alterations that drive malignant mesothelioma have recently been determined, the molecular pathogenesis of well-differentiated papillary mesothelioma is unknown. Here we performed genomic profiling on a cohort of ten well-differentiated papillary mesothelioma of the peritoneum. We identified that all tumors harbored somatic missense mutations in either the TRAF7 or CDC42 genes, and lacked alterations involving BAP1, NF2, CDKN2A, DDX3X, SETD2, and ALK that are frequent in malignant mesothelioma. We recently identified that another mesothelial neoplasm, adenomatoid tumor of the genital tract, is genetically defined by somatic missense mutations in the TRAF7 gene, indicating a shared molecular pathogenesis between well-differentiated papillary mesothelioma and adenomatoid tumors. To the best of our knowledge, well-differentiated papillary mesothelioma is the first human tumor type found to harbor recurrent mutations in the CDC42 gene, which encodes a Rho family GTPase. Immunohistochemistry demonstrated intact BAP1 expression in all cases of well-differentiated papillary mesothelioma, indicating that this is a reliable marker for distinguishing well-differentiated papillary mesothelioma from malignant mesotheliomas that frequently display loss of expression. Additionally, all well-differentiated papillary mesothelioma demonstrated robust expression of L1 cell adhesion molecule (L1CAM), a marker of NF-kB pathway activation, similar to that observed in adenomatoid tumors. In contrast, we have previously shown that L1CAM staining is not observed in normal mesothelial cells and malignant mesotheliomas of the peritoneum. Together, these studies demonstrate that well-differentiated papillary mesothelioma is genetically defined by mutually exclusive mutations in TRAF7 and CDC42 that molecularly distinguish this entity from malignant mesothelioma.

Well-Differentiated Papillary Mesothelioma of the Peritoneum Is Genetically Distinct from Malignant Mesothelioma

“…What is surprising in our results is the absence of the TRAF7 and CDC42 alterations reported by Yu et al [7] and Stevers et al [11] in WDPM and by the same group in adenomatoid tumors [29]. Alterations in TRAF7 have also been reported in malignant mesotheliomas [4,16,30].…”

“…Nevertheless, using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), Lee et al demonstrated that, unlike in malignant mesothelioma, both BAP1 and CDKN2A are intact and respective proteins are expressed in WDPMs [10]. More recently, Stevers et al [11] performed genomic profiling of 10 WDPMs and found that they harbored TRAF7 or CDC42 mutually exclusive missense mutations.…”

Molecular characterization of localized pleural mesothelioma

“…TRAF7, a member in the tumor necrosis factor (TNF) receptor-associated factor family, is an E3-ubiquitin ligase in the NF-kB signaling pathway to regulate diverse processes such as transcription, survival, and cytokine production. Recurrent mutations in TRAF7 are present in a subset of meningiomas [32][33][34], intraneural perineuriomas [35], well-differentiated papillary mesotheliomas [36,37], most adenomatoid tumors of the genital type [38,39], and rare cases of diffuse malignant pleural mesothelioma [7]. The two TRAF7 mutations p.S561R and p.Q613E in localized pleural mesotheliomas are located in one of the seven Cterminal WD40 domain repeats.…”

Well-Differentiated Papillary Mesothelioma of the Peritoneum is Genetically Distinct from Malignant Mesothelioma

“…Copy-number loss of BAP1, CDKN2A/B, LAST1/2, and NF2 is frequently found in pleural mesothelioma 4,5 . 11 What is surprising in our results is the absence of the TRAF7 and CDC42 alterations reported by Yu et al 7 and Stevers et al 11 in WDPM and by the same group in adenomatoid tumors 31 . Alterations in TRAF7 has also been reported in malignant mesotheliomas 4,20,32…”