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. 2020 Jun 13;12(6):1568.
doi: 10.3390/cancers12061568.

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

Raunak Shrestha  1   2   3 , Noushin Nabavi  1   4 , Stanislav Volik  1 , Shawn Anderson  1 , Anne Haegert  1 , Brian McConeghy  1 , Funda Sar  1 , Sonal Brahmbhatt  1 , Robert Bell  1 , Stephane Le Bihan  1 , Yuzhuo Wang  1   2   4 , Colin Collins  1   2 , Andrew Churg  5
Affiliations

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

Raunak Shrestha et al. Cancers (Basel). .

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.

Keywords: DNA sequencing; WDPM; malignant mesothelioma; mutation; well-differentiated papillary mesothelioma.

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Histopathology of five WDPM cases used for the study. Microphotographs of histological features of WDPM stained using haematoxylin and eosin (H&E). The panel under the dotted box represents the magnified section of the photomicrographs at ×20. The lesion sites/sizes were peritoneum, site not specified, for cases WDPM-01 (3 mm), WDPM-02 (6 mm), WDPM-03 (4 mm), WDPM-04 mesentery (4 mm), and WDPM-05 omentum (4 mm).
Figure 2
Figure 2
Landscape of mutations in WDPM. (A) Mutational signature present in WDPM. (B) Proportional contribution of different COSMIC mutational signature per sample. (C) Mutation status in WDPM. Top seven most recurrent mutations are represented in the figure. The bar plot on the top panel represents the total number of mutations detected in the respective WDPM. (D–H) Plots showing mutation distribution and the protein domains for the corresponding mutated protein.
Figure 3
Figure 3
Signaling pathways dysregulated in WDPM. We performed pathway enrichment analysis using genes mutated in WDPM cases against the signaling pathways in the KEGG pathway database. The figure shows the top 20 pathways enriched with mutated genes in WDPM. Each circle represents a pathway, its size indicates the number of mutated genes targeting the pathway, and its color indicates the pathway enrichment score. The thickness of edges connecting two circles (pathways) is proportional to the number of mutated genes common between the two pathways. PI signaling: phosphatidylinositol signaling pathway.
Figure 4
Figure 4
Genomic alterations in WDPM and peritoneal mesothelioma. We compared the genomic alteration profile of the WDPM cases to the peritoneal mesothelioma patient cohorts from two recently published studies, Vancouver Prostate Centre (VPC) cohort [6] and American Association for Cancer Research (AACR) project Genomics Evidence Neoplasia Information Exchange (GENIE) cohort [16]. (A) Oncoplot showing differences in mutation pattern between WDPM and peritoneal mesothelioma. Each column in the figure represents an individual cancer sample. (B) Oncoplot showing the copy number aberration status of WDPM and peritoneal mesothelioma. Each column in the figure represents an individual cancer sample.
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