EWSR1::YY1 fusion positive peritoneal epithelioid mesothelioma harbors mesothelioma epigenetic signature: Report of 3 cases in support of an emerging entity

Our plain-English summary of EWSR1::YY1 fusion positive peritoneal epithelioid mesothelioma harbors mesothelioma epigenetic signature: Report of 3 cases in support of an emerging entity, by J.K. Dermawan, D. Torrence, C.H. Lee, et al (Genes, Chromosomes & Cancer, 2022).

The study

• Authors: J.K. Dermawan, D. Torrence, C.H. Lee, L. Villafania, K.A. Mullaney, S. DiNapoli, P. Sukhadia, R. Benayed, L. Borsu, N.P. Agaram, G.M. Nash, B.C. Dickson, J. Benhamida, C.R. Antonescu
• Journal: Genes, Chromosomes & Cancer
• Published: 2022;61(10):592-602
• Type of article: Case report
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma is a rare, aggressive malignant neoplasm of mesothelial origin. A small subset of peritoneal mesothelioma is driven by recurrent gene fusions, mostly EWSR1/FUS::ATF1 fusions, with predilection for young adults. To date, only two cases of mesothelioma harboring EWSR1::YY1 fusions have been described. We present three additional cases of EWSR1::YY1-fused peritoneal mesotheliomas, two localized and one diffuse, all occurring in the peritoneum of middle-aged adults (2 females and 1 male), and discovered incidentally by imaging or during surgery performed for unrelated reasons. None presented with symptoms or had a known history of asbestos exposure. All three cases were cellular epithelioid neoplasms with heterogeneous architectural patterns comprising mostly solid nests and sheets with variably papillary and trabecular areas against collagenous stroma. Cytologically, the cells were monomorphic, polygonal, epithelioid cells with dense eosinophilic cytoplasm and centrally located nuclei. Overt mitotic activity or tumor necrosis was absent. All cases showed strong diffuse immunoreactivity for pancytokeratin, CK7, and nuclear WT1, patchy to negative calretinin, retained BAP1 expression, and were negative for Ber-EP4 and MOC31. RNA-sequencing confirmed in-frame gene fusion transcripts involving EWSR1 exon 7/8 and YY1 exon 2/3. By unsupervised clustering analysis, the methylation profiles of EWSR1::YY1-fused mesotheliomas clustered similarly with EWSR1/FUS::ATF1-fused mesotheliomas and conventional mesotheliomas, suggesting a mesothelioma epigenetic signature. All three patients underwent surgical resection or cytoreductive surgery of the masses. On follow-up imaging, no recurrence or progression of disease was identified. Our findings suggest that EWSR1::YY1-fusion defines a small subset of peritoneal epithelioid mesothelioma in middle-aged adults without history of asbestos exposure.

© 2022 Wiley Periodicals LLC.

In plain English

This report described three patients with peritoneal mesothelioma (mesothelioma of the abdominal lining) whose tumors carried a gene fusion called EWSR1::YY1. The fusion had previously been reported in only two patients. The three were a 56-year-old woman, a 49-year-old man and a 67-year-old woman. None had a known history of asbestos exposure and none had symptoms. Their tumors were found incidentally, on imaging or during a hernia repair. Two tumors were localized and one was diffuse. Under the microscope all three were epithelioid, and all retained the BAP1 protein. Genetic testing confirmed the fusion in all three. The authors also compared DNA methylation patterns across 358 tumor samples. Two of the cases clustered with conventional mesotheliomas and with mesotheliomas carrying a different fusion, apart from lung and colorectal adenocarcinomas. All three patients had surgery, and follow-up imaging showed no recurrence or progression. The authors concluded that the findings support EWSR1::YY1 as a recurrent genetic change in epithelioid peritoneal mesothelioma. They said further profiling studies are needed to determine whether these tumors are a distinct entity, and larger, long-term studies are needed to investigate their outlook.

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: Case series of 3 patients, with microscopic, immunohistochemical, RNA sequencing and DNA methylation analyses
• Who was studied: Three middle-aged adults (two women, one man; ages 56, 49 and 67) with peritoneal mesothelioma carrying an EWSR1::YY1 fusion. The study was approved by the Memorial Sloan Kettering Institutional Review Board. Dates of diagnosis are not stated.
• Exposure: No asbestos or other exposure was studied. The paper concerns a gene fusion (EWSR1::YY1). None of the three patients had a known history of asbestos exposure.
• Main results:
  • None of the 3 patients had a known history of asbestos exposure, and none had symptoms from the disease when it was found.
  • Cases 1 and 3 were classified as localized peritoneal mesothelioma, and case 2 was classified as diffuse peritoneal mesothelioma.
  • All three tumors stained strongly and diffusely for pan-cytokeratin, CK7 and nuclear WT1. They showed patchy to negative calretinin and retained BAP1 expression.
  • Two cases had an EWSR1 (exon 8) to YY1 (exon 3) fusion, and one case had an EWSR1 (exon 7) to YY1 (exon 2) fusion.
  • Methylation data were analyzed for 358 samples in total. The two EWSR1::YY1 cases tested (cases 1 and 2) and three EWSR1/FUS::ATF1-fused mesotheliomas clustered with conventional mesotheliomas.
  • In both clustering methods, all three types of mesothelioma were distinct from lung adenocarcinomas and colorectal adenocarcinomas.
  • One soft tissue tumor type, angiomatoid fibrous histiocytoma (AFH), appeared related to mesothelioma in the clustering.
  • All three patients had surgical resection or cytoreductive surgery. No recurrence or progression was seen on follow-up imaging.
• The authors' conclusion: The authors concluded that these 3 cases support EWSR1::YY1 being a recurrent genetic alteration in epithelioid peritoneal mesothelioma. They said that whether these tumors are a distinct entity warrants further investigation, possibly involving transcriptomic and additional epigenetic profiling.
• Limitations the authors state:
  • Retained BAP1 may distinguish these tumors from conventional mesotheliomas, but confirming this requires larger studies. BAP1 was not tested in the 2 earlier cases.
  • Confirming a mesothelial methylation signature would require comparison with normal mesothelium and with benign or reactive mesothelial lesions. The authors could not obtain such data.
  • Long-term studies with larger numbers of patients are needed to establish the prognosis of these tumors.

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: Epithelioid, Mesothelioma, Neoplasm, Peritoneal Mesothelioma, Peritoneum, Asbestos Exposure, Trabecular, Eosinophilic.

Related studies

• RNA sequencing identifies fusion of the EWSR1 and YY1 genes in mesothelioma with t(14;22)(q32;q12) — I. Panagopoulos, J. Thorsen, et al. (2013)
• Malignant Mesothelioma With EWSR1-ATF1 Fusion in Two Adolescent Male Patients — H. Ren, S.R. Rassekh, et al. (2021)
• A Subset of Malignant Mesotheliomas in Young Adults Are Associated With Recurrent EWSR1/FUS-ATF1 Fusions — P. Desmeules, P. Joubert, et al. (2017)
• Genomic profiling of malignant peritoneal mesothelioma reveals recurrent alterations in epigenetic regulatory genes BAP1, SETD2, and DDX3X — N.M. Joseph, Y.Y. Chen, et al. (2017)
• Malignant Peritoneal Mesothelioma With EWSR1-ATF1 Fusion: A Case Report — H. Ke, A.J. Gill, et al. (2021)
• Generation of human embryonic stem cell models to exploit the EWSR1-CREB fusion promiscuity as a common pathway of transformation in human tumors — F. Vanoli, B. Meskauskaite, et al. (2021)

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