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

Our plain-English summary of Well-Differentiated Papillary Mesothelioma of the Peritoneum Is Genetically Distinct from Malignant Mesothelioma, by R. Shrestha, N. Nabavi, S. Volik, et al (Cancers, 2020).

The study

• Authors: R. Shrestha, N. Nabavi, S. Volik, S. Anderson, A. Haegert, B. McConeghy, F. Sar, S. Brahmbhatt, R. Bell, S. Le Bihan, Y. Wang, C. Collins, A. Churg
• Journal: Cancers
• Published: 2020;12(6)
• Cited by: 34 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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 EHD1, ATM, FBXO10, SH2D2A, CDH5, MAGED1, and TP73 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 BAP1, SETD2, NF2, CDKN2A/B, LASTS1/2, PBRM1, and SMARCC1 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.

In plain English

This laboratory study looked at the genes of well-differentiated papillary mesothelioma (WDPM), an uncommon growth of the cells lining the abdominal cavity (peritoneum) that is usually found by chance. The authors sequenced DNA from five WDPMs kept in the pathology archives of Vancouver General Hospital. All five were found during surgery for another condition. The authors compared these tumors with published genetic data on malignant peritoneal mesothelioma. Asbestos exposure was not studied; the authors considered prior exposure to carcinogens, including asbestos, extremely unlikely. They found 461 mutations across the five tumors, affecting 297 genes. Two genes, FBXO10 and SH2D2A, were mutated in all five, and mutations in EHD1, ATM, CDH5, MAGED1 and TP73 were each found in four. The WDPMs showed a strong excess of C-to-A DNA changes, unlike the C-to-T pattern in peritoneal mesothelioma. They also lacked the BAP1, SETD2, NF2 and CDKN2A changes common in malignant mesothelioma. The authors concluded that WDPMs are tumors genetically distinct from malignant mesotheliomas that do not appear to be their precursors. They noted that normal tissue mixed into the samples lowered detection sensitivity, and they called for larger studies.

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 genetic study: whole exome sequencing of archived tumor tissue (formalin-fixed, paraffin-embedded), compared with published sequencing data from two peritoneal mesothelioma patient cohorts
• Who was studied: Five well-differentiated papillary mesotheliomas of the peritoneum, all solitary lesions (3 to 6 mm), found incidentally during surgery for another process, taken from the surgical pathology archives of Vancouver General Hospital, Canada; dates not given. For comparison, the authors used two published peritoneal mesothelioma cohorts (the VPC cohort and the AACR Project GENIE cohort).
• Exposure: No asbestos or other exposure was measured. The authors stated that prior exposure to carcinogens (aflatoxin or asbestos) was extremely unlikely in these incidentally found cases.
• Main results:
  • Across the five WDPMs, 461 unique non-silent mutations were found, affecting 297 unique protein-coding genes
  • FBXO10 and SH2D2A were mutated in all five WDPM cases
  • The EHD1 D147A mutation was found in four of the five cases; the same four cases with ATM mutations all carried ATM K2303R; mutations in MAGED1 and TP73 were also each found in four cases
  • Mutational signature 24 (from the COSMIC database) was significantly operative in all five WDPM cases
  • WDPM showed strong enrichment of C to A transversion mutations, whereas the comparison peritoneal mesotheliomas showed strong enrichment of C to T transition mutations
  • None of the five WDPMs had the mutations in BAP1, SETD2, TP53, NF2, CDKN2A or LATS1/2 frequently seen in malignant mesotheliomas
  • No copy number loss was found in the WDPMs in genes characteristic of malignant mesotheliomas, such as BAP1, SETD2, PBRM1, SMARCC1, CDKN2A/B, LATS1/2 and NF2
  • Unlike an earlier study by Stevers et al., this study found no high-confidence mutations in TRAF7 or CDC42 in the five WDPMs
• The authors' conclusion: The authors concluded that WDPMs are neoplasms that are genetically distinct from malignant mesotheliomas and, based on the mutations observed, do not appear to be precursors of malignant mesotheliomas. They added that, together with data from Stevers et al., the findings reinforce the idea that WDPM should not be treated in the same way as malignant mesothelioma.
• Limitations the authors state:
  • Tumor cellularity was only about 50%, and the admixture of normal tissue lowered the sensitivity for detecting mutations
  • No matched normal (germline) samples were available from the WDPM patients; blood DNA from peritoneal mesothelioma patients was used instead as the control
  • Sequencing many genes came at the cost of lower sequencing depth than the targeted panel used by Stevers et al.
  • The results differed from those of Stevers et al. The authors suggested this may reflect genetic variation among WDPMs and said it needs study in larger groups of patients.

Topics

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

Related studies

• Well-differentiated papillary mesothelioma of the peritoneum is genetically defined by mutually exclusive mutations in TRAF7 and CDC42 — M. Stevers, J.T. Rabban, et al. (2019)
• 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)
• Aberrant Pax-8 expression in well-differentiated papillary mesothelioma and malignant mesothelioma of the peritoneum: a clinicopathologic study — D. Xing, N. Banet, et al. (2018)
• Well-differentiated papillary mesothelioma of the peritoneum: a separate entity — K. Hoekman, G. Tognon, et al. (1996)
• Therapeutic strategies for well-differentiated papillary mesothelioma of the peritoneum — Y.K. Lee, H.J. Jun, et al. (2013)

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