NF2 alteration in mesothelioma

Our plain-English summary of NF2 alteration in mesothelioma, by Y. Sekido, T. Sato (Frontiers in Toxicology, 2023).

The study

• Authors: Y. Sekido, T. Sato
• Journal: Frontiers in Toxicology
• Published: 2023;5:1161995
• Type of article: Review
• Cited by: 29 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The NF2 tumor suppressor gene is a frequent somatically mutated gene in mesothelioma, with 30%-40% mesotheliomas showing NF2 inactivation. NF2 encodes merlin, a member of the ezrin, radixin, and moesin (ERM) family of proteins that regulate cytoskeleton and cell signaling. Recent genome analysis revealed that NF2 alteration may be a late event in mesothelioma development, suggesting that NF2 mutation confers a more aggressive phenotype to mesothelioma cells and may not be directly caused by asbestos exposure. The Hippo tumor-suppressive and mTOR prooncogenic signaling pathways are crucial cell-signaling cascades regulated by merlin. Although the exact role and timing of NF2 inactivation in mesothelioma cells remain to be elucidated, targeting the NF2/merlin-Hippo pathway may be a new therapeutic strategy for patients with mesothelioma.

Copyright © 2023 Sekido and Sato.

In plain English

This mini review summarized published research on the NF2 gene in mesothelioma. The authors reported no new patients or experiments. NF2 makes merlin, a protein that helps restrain cell growth, partly through the Hippo signaling pathway. Citing earlier studies, the authors noted NF2 mutations in 30%–40% of pleural and 21%–35% of peritoneal mesotheliomas, found more often in sarcomatoid than in epithelioid tumors. Studies that sampled several sites of the same tumor found BAP1/3p21 loss to be an early event and NF2/22q loss a late one. People born with NF2 mutations did not seem to have a significantly increased mesothelioma risk. In one cited mouse study, mice lacking one copy of Nf2 developed mesothelioma faster after asbestos exposure than normal littermates also exposed to asbestos. Trials of the drugs everolimus and defactinib in pleural mesothelioma showed limited or no clinical benefit. The authors concluded that NF2 alteration may occur late and may not be directly caused by asbestos exposure, and that its exact role and timing remain to be clarified.

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: Mini review of published studies (no original data)
• Who was studied: No study population of its own. The review drew on published genomic studies of human pleural and peritoneal mesothelioma tumors, cell-line and mouse experiments, and clinical drug trials.
• Exposure: The review's subject was NF2 gene alteration, not measured exposure. Asbestos was discussed as a possible cause, with no fiber type named. One cited mouse study involved asbestos exposure.
• Main results:
  • In cited studies, somatic NF2 mutation was found in 30%–40% of pleural mesotheliomas.
  • Peritoneal mesothelioma makes up 10%–20% of all mesothelioma cases, and NF2 mutation was seen in 21%–35% of peritoneal cases in cited studies.
  • A cited study reported NF2 mutations more frequently in sarcomatoid than in epithelioid mesothelioma.
  • In a cited multi-sample genome study, BAP1/3p21 loss was an early event and NF2/22q loss a late event.
  • In two cited multi-sample studies, 22% (Zhang et al., 2021) and 38% (Meiller et al., 2021) of detected NF2 mutations were subclonal, meaning present in only part of the tumor.
  • Patients and carriers of the inherited NF2 cancer syndrome did not seem to have a significantly increased risk of mesothelioma, according to a cited source.
  • In a cited mouse study, Nf2 (+/−) knockout mice showed accelerated mesothelioma formation after asbestos exposure compared with wild-type littermates given asbestos only.
  • A cited immunohistochemistry study found merlin expression absent in 52% of all pleural mesotheliomas and 70% of non-epithelioid tumors.
  • Cited phase-II trials found limited clinical activity for everolimus in advanced pleural mesothelioma, and no confirmed benefit for defactinib as maintenance therapy for pleural mesothelioma.
• The authors' conclusion: The authors concluded that NF2 alteration is a key genetic change in mesothelioma that may occur late, as a subclonal event, and may not be directly induced by asbestos exposure. They described the Hippo pathway regulated by merlin as a promising treatment target.
• Limitations the authors state:
  • The authors stated that the roles and timing of NF2 inactivation in mesothelioma cells are not yet fully understood.
  • The authors noted that NF2 alteration frequencies may be underestimated, because whole-exome sequencing alone cannot detect translocations and large deletions of NF2, and subclonal mutations can be missed depending on which tumor tissue is analyzed.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Tumor Suppressor Gene, Merlin, Asbestos Exposure.

Related studies

• Aberrant expression of NPPB through YAP1 and TAZ activation in mesothelioma with Hippo pathway gene alterations — T. Sato, K. Akao, et al. (2023)
• Fenton reaction induced cancer in wild type rats recapitulates genomic alterations observed in human cancer — S. Akatsuka, Y. Yamashita, et al. (2012)
• Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations — R. Bueno, E.W. Stawiski, et al. (2016)
• Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma — G. Guo, J. Chmielecki, et al. (2015)
• High Incidence of Somatic BAP1 alterations in sporadic malignant mesothelioma — M. Nasu, M. Emi, et al. (2015)
• Asbestos, chromosomal deletions, and tumor suppressor gene alterations in human malignant mesothelioma — S.S. Murthy, J.R. Testa (1999)

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