Update on gene fusions and the emerging clinicopathological landscape of peritoneal and pleural mesotheliomas and other neoplasms

Our plain-English summary of Update on gene fusions and the emerging clinicopathological landscape of peritoneal and pleural mesotheliomas and other neoplasms, by N. Benzerdjeb, P. Dartigues, V. Kepenekian, et al (ESMO Open, 2024).

The study

• Authors: N. Benzerdjeb, P. Dartigues, V. Kepenekian, F. Damiola, R. Sequeiros, F. Galateau-Salle, H. Begueret, E. Mery, D. Damotte, V. Verriele, J. Fontaine, S. Isaac, S. Valmary-Degano, L. Villeneuve, O. Glehen, A. Scherpereel, F. Forest, A. De la Fourchardiere, S. Paindavoine, A. Hourlier, D. Pissaloux, F. Tirode, S. Lantuejoul, RENAPE and the NETMESO/MESOPATH Networks
• Journal: ESMO Open
• Published: 2024;9(8):103644
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Mesothelioma is a rare and aggressive malignant neoplasm arising from mesothelial cells, which occasionally manifests recurrent fusions. EWSR1/FUS-CREB, YY1, MAP3K8, NR4A3, and ALK-rearranged proliferations have been reported in limited series with no clear histological or clinical correlations, limiting clinicians' ability to assess prognosis and integrate these new entities into therapeutic decisions. The aim of this study was to better characterize these rearranged proliferations histologically, molecularly, and clinically.

Methods: Clinical, pathological, and comprehensive transcriptome and mutation data were collected for each case.

Results: A total of 41 tumors were included, encompassing 7 ALK, 10 MAP3K8, 4 NR4A3, 8 ESWR1/FUS::ATF1, 8 EWSR1::YY1, and 4 SUFU-fused cases. We found a female predominance, except for cases harboring NR4A3 and SUFU; and most patients were around 60 years of age, but those harboring ALK or EWSR1/FUS::ATF1 gene fusions were younger. Each group exhibited distinct histological, immunohistochemical, molecular features, and oncological courses. Specifically, MAP3K8 and ALK presented PAX8+ papillary proliferations, ESWR1/FUS::ATF1 and EWSR1::YY1 displayed angiomatoid fibrous histiocytoma-like patterns, while SUFU showcased 'tissue culture'-like spindle cell proliferation. Poor prognosis factors were the pleural site, male sex, Ki67 ≥10%, and ESWR1/FUS::ATF1 or SUFU gene fusions.

Conclusions: This study significantly broadens the spectrum of mesothelial tumors associated with fusions, offering insight into novel epithelioid (mesothelial) proliferations with distinctive histological appearances, molecular profiles, and prognoses to guide adapted treatments for patients.

Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.

In plain English

This French study described 41 fusion-carrying tumors of the peritoneum, pleura and tunica vaginalis testis from the RENAPE and NETMESO/MESOPATH networks. The authors reviewed the tissue, used immunohistochemical stains and RNA sequencing, and compared gene-expression profiles with 160 control tumors without fusions. The article reported nothing about asbestos or other fiber exposure. The tumors had 7 ALK, 10 MAP3K8, 4 NR4A3, 8 EWSR1/FUS::ATF1, 8 EWSR1::YY1 and 4 SUFU fusions. In univariate analysis, four factors were associated with longer overall survival: female sex, a peritoneal or tunica vaginalis testis site, a Ki67 proliferation index below 10%, and fusion type (ALK or NR4A3 in the text; the figure legend adds MAP3K8). No deaths or recurrences were recorded in the ALK group (all female, mean age 27.8 years) or the NR4A3 group. Both pleural MAP3K8 patients died within a month of diagnosis. All four SUFU patients, all with pleural tumors, died. Most fusion groups formed distinct gene-expression clusters, while SUFU tumors clustered with some pleural mesotheliomas. The authors concluded that the study broadens the spectrum of mesothelial tumors associated with fusions.

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: Retrospective clinicopathological and molecular case series of fusion-carrying tumors, with gene-expression comparison against control tumors without fusions
• Who was studied: 41 patients treated for tumors with gene fusions (mesotheliomas/neoplasms), with tissue from the French MESOBANK reviewed by the RENAPE and NETMESO/MESOPATH networks in France, plus 160 control patients with tumors without fusions. Study dates are not given.
• Exposure: This is not an asbestos exposure study, and no fiber exposure was reported. The study examined tumors carrying gene fusions (ALK, MAP3K8, NR4A3, EWSR1/FUS::ATF1, EWSR1::YY1, SUFU).
• Main results:
  • The 41 fusion tumors comprised 7 ALK-rearranged epithelioid mesotheliomas, 10 MAP3K8, 4 NR4A3, 8 EWSR1/FUS::ATF1 epithelioid tumors, 8 EWSR1::YY1 and 4 SUFU-rearranged sarcomatoid mesotheliomas.
  • In univariate analysis of the fusion cases, female sex (P 0.0346) and a peritoneal or tunica vaginalis testis site (P less than 0.001) were associated with longer overall survival.
  • A Ki67 proliferation index below 10% was associated with longer overall survival (P less than 0.001).
  • Fusion type was also associated with longer overall survival (P 0.016). The results text names ALK or NR4A3 fusions, while the Figure 1 legend names ALK, MAP3K8 or NR4A3.
  • In the ALK group (7 patients, all female, mean age 27.8 years), there was no death or recurrence over a mean follow-up of 56.7 months.
  • The two pleural MAP3K8-rearranged patients died in the month after diagnosis. Both of these cases had TP53 mutations.
  • In the NR4A3 group (4 patients, all peritoneal), there was no death or recurrence over a mean follow-up of 60.8 months.
  • In the SUFU group (4 patients, all pleural), all patients died. Mean follow-up was 17.5 months.
  • On gene-expression clustering, ALK, NR4A3 and MAP3K8 tumors formed distinct subgroups, while SUFU-rearranged sarcomatoid mesotheliomas clustered with some pleural mesotheliomas.
• The authors' conclusion: The authors concluded that the study broadens the spectrum of mesothelial tumors associated with fusions. In their view, it offers insight into new proliferations with distinctive histology, molecular profiles and prognoses that could guide adapted treatments.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Neoplasm, Mesothelioma, Mesothelial Cells, Prognosis, Spindle Cell, Epithelioid.

Related studies

• Pediatric Mesothelioma With ALK Fusions: A Molecular and Pathologic Study of 5 Cases — P. Argani, D.W.Q. Lian, et al. (2021)
• Tertiary lymphoid structures in epithelioid malignant peritoneal mesothelioma are associated with neoadjuvant chemotherapy, but not with prognosis — N. Benzerdjeb, P. Dartigues, et al. (2021)
• EWSR1::YY1 fusion positive peritoneal epithelioid mesothelioma harbors mesothelioma epigenetic signature: Report of 3 cases in support of an emerging entity — J.K. Dermawan, D. Torrence, et al. (2022)
• Combined grade and nuclear grade are prognosis predictors of epithelioid malignant peritoneal mesothelioma: a multi-institutional retrospective study — N. Benzerdjeb, P. Dartigues, et al. (2021)
• Case report: targeted therapy of malignant pleural mesothelioma with anaplastic lymphoma kinase receptor tyrosine kinase gene fusion mutation by crizotinib — Y. Wu, Y. Zhao, et al. (2024)
• Immunohistochemical evaluation of two antibodies against PD-L1 and prognostic significance of PD-L1 expression in epithelioid peritoneal malignant mesothelioma: A RENAPE study — S. Valmary-Degano, P. Colpart, et al. (2017)

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