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.