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

Our plain-English summary of Well-differentiated papillary mesothelioma of the peritoneum is genetically defined by mutually exclusive mutations in TRAF7 and CDC42, by M. Stevers, J.T. Rabban, K. Garg, et al (Modern Pathology, 2019).

The study

• Authors: M. Stevers, J.T. Rabban, K. Garg, J. Van Ziffle, C. Onodera, J.P. Grenert, I. Yeh, B.C. Bastian, C. Zaloudek, D.A. Solomon
• Journal: Modern Pathology
• Published: 2019;32(1):88-99
• Cited by: 80 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study examined the genes of ten well-differentiated papillary mesotheliomas of the peritoneum, an uncommon tumor of the abdominal lining. The cases came from the pathology archives of the University of California, San Francisco, from 1993 to 2014. The patients were three men and seven women aged 54 to 84. Each tumor had been found by chance during surgery for another condition. The authors sequenced all ten tumors, plus normal tissue from nine patients. All ten tumors carried a mutation in one of two genes, TRAF7 in seven and CDC42 in three, never both. None had changes in BAP1 or in other genes the authors list as common in malignant mesothelioma. In the nine tumors that were stained, BAP1 protein was intact and L1CAM protein was strongly present. No patient had a recurrence over a median follow-up of 3.1 years. The study did not examine asbestos exposure. The introduction states, as background, that this tumor type is not associated with it. The authors concluded that this tumor appears genetically distinct from malignant mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory genomic study (case series) of archived tumor specimens. The authors used targeted next-generation DNA sequencing of all ten tumors, compared against matched normal tissue where it was available (nine patients), plus immunohistochemistry.
• Who was studied: Ten patients (three male, seven female, aged 54 to 84 years, median 66) with well-differentiated papillary mesothelioma of the peritoneum. Cases were retrieved from the pathology archives of the University of California, San Francisco, spanning 1993 to 2014. All tumors were found incidentally during surgery for other conditions.
• Exposure: Asbestos exposure was not studied. The study looked at gene mutations in the tumors. The introduction states, as background and not as a finding of this study, that this tumor type is not associated with prior asbestos exposure.
• Main results:
  • All 10 tumors had somatic missense mutations in either TRAF7 or CDC42, and the two never occurred together: 7 tumors had TRAF7 mutations and 3 had CDC42 mutations.
  • The mutations were confirmed to be tumor-specific (somatic) in all 9 cases that had matched normal tissue available.
  • None of the 10 tumors had alterations in BAP1, NF2, CDKN2A, DDX3X, SETD2, TP53 or ALK, genes the authors describe as commonly altered in malignant mesotheliomas of the pleural and peritoneal cavities.
  • All tumors had a low total somatic mutation burden.
  • In all 9 tumors with tissue available for staining, BAP1 protein expression was intact.
  • All 9 stained tumors, including both TRAF7-mutant and CDC42-mutant cases, showed strong membranous staining for L1CAM protein.
  • No patient in the cohort had disease recurrence over a median clinical follow-up of 3.1 years.
  • The authors concluded that this tumor appears genetically distinct from malignant mesothelioma.
• The authors' conclusion: The authors concluded that combining BAP1 and L1CAM staining is likely to be a reliable way to tell well-differentiated papillary mesothelioma apart from malignant mesothelioma in the majority of cases.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Well-Differentiated Papillary Mesothelioma, Peritoneum, Neoplasm, Peritoneal Cavity, Malignant Mesothelioma, Biomarker, BAP1, CDKN2A.

Related studies

• Adenomatoid tumors of the male and female genital tract are defined by TRAF7 mutations that drive aberrant NF-kB pathway activation — B. Goode, N.M. Joseph, et al. (2018)
• TRAF7 mutations and immunohistochemical study of uterine adenomatoid tumor compared with malignant mesothelioma — H. Itami, T. Fujii, et al. (2021)
• First somatic mutation of E2F1 in a critical DNA binding residue discovered in well-differentiated papillary mesothelioma of the peritoneum — W. Yu, W. Chan-On, et al. (2011)
• Well-differentiated papillary mesothelioma of the female peritoneum: a clinicopathologic study of 26 cases — A. Malpica, S. Sant'Ambrogio, et al. (2012)
• Well-differentiated papillary mesothelioma of the peritoneum: a pathological analysis and review of the literature — A.V. Hoekstra, M.W. Riben, et al. (2005)
• Well-differentiated papillary mesothelioma of the peritoneum: a separate entity — K. Hoekman, G. Tognon, et al. (1996)

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