High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas

Our plain-English summary of High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas, by A.B. Bianchi, S.I. Mitsunaga, J.Q. Cheng, et al (Proceedings of the National Academy of Sciences of the United States of America, 1995).

The study

• Authors: A.B. Bianchi, S.I. Mitsunaga, J.Q. Cheng, W.M. Klein, S.C. Jhanwar, B. Seizinger, N. Kley, A.J. Klein-Szanto, J.R. Testa
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Published: 1995;92(24):10854-8
• Cited by: 270 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesotheliomas (MMs) are aggressive tumors that develop most frequently in the pleura of patients exposed to asbestos. In contrast to many other cancers, relatively few molecular alterations have been described in MMs. The most frequent numerical cytogenetic abnormality in MMs is loss of chromosome 22. The neurofibromatosis type 2 gene (NF2) is a tumor suppressor gene assigned to chromosome 22q which plays an important role in the development of familial and spontaneous tumors of neuroectodermal origin. Although MMs have a different histogenic derivation, the frequent abnormalities of chromosome 22 warranted an investigation of the NF2 gene in these tumors. Both cDNAs from 15 MM cell lines and genomic DNAs from 7 matched primary tumors were analyzed for mutations within the NF2 coding region. NF2 mutations predicting either interstitial in-frame deletions or truncation of the NF2-encoded protein (merlin) were detected in eight cell lines (53%), six of which were confirmed in primary tumor DNAs. In two samples that showed NF2 gene transcript alterations, no genomic DNA mutations were detected, suggesting that aberrant splicing may constitute an additional mechanism for merlin inactivation. These findings implicate NF2 in the oncogenesis of primary MMs and provide evidence that this gene can be involved in the development of tumors other than nervous system neoplasms characteristic of the NF2 disorder. In addition, unlike NF2-related tumors, MM derives from the mesoderm; malignancies of this origin have not previously been associated with frequent alterations of the NF2 gene.

In plain English

This was a laboratory study of the neurofibromatosis type 2 gene (NF2), a tumor suppressor gene on chromosome 22, in malignant mesothelioma. The authors examined 15 mesothelioma cell lines grown from surgically removed tumors, plus the matching original tumor tissue where it was available, and compared them with normal mesothelial cells. The study did not measure asbestos exposure. Abnormal NF2 patterns were found in 8 of the 15 cell lines (53%). Seven of those eight had matched tumor tissue, and the same mutation was confirmed in 6 of the 7. Six of the eight changes were predicted to cut short the gene's protein, called merlin, and two to delete a stretch from inside it. In two cell lines the change seen in the gene message was not found in the DNA. For one of these, the authors suggested the change may have come from faulty processing (aberrant splicing) of the message. Six of the eight tumors with changes were of the biphasic type. The authors concluded that their findings clearly implicate NF2 in the development of mesothelioma.

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: mesothelioma cell lines and matched primary tumor samples screened for NF2 gene mutations
• Who was studied: 15 human malignant mesothelioma cell lines established from surgically resected tumors, 7 matched primary tumor samples, and a normal human mesothelial cell strain (LP-9) as control. Location and dates of the patients are not given.
• Exposure: No asbestos exposure was studied or measured. The study examined NF2 gene alterations. Asbestos is mentioned only as background on mesothelioma.
• Main results:
  • Abnormal NF2 patterns were found in 8 of 15 (53%) mesothelioma cell lines.
  • Of the 7 cell lines with alterations that had matched primary tumors, the NF2 mutation was confirmed in 6 of the 7 primary tumors.
  • In two cell lines (222 and 1-53), the alterations in the gene message were not found at the DNA level.
  • For cell line 222, the authors suggested the altered message may have resulted from aberrant splicing.
  • Two of the eight alterations were predicted to cause in-frame deletions within the merlin protein. The remaining six were predicted to truncate (cut short) the protein.
  • Of the 8 tumors with NF2 alterations, 6 were biphasic. Of the 7 tumors with normal NF2, 6 were epithelioid or sarcomatous and only 1 was biphasic.
• The authors' conclusion: The authors concluded that their findings clearly implicate NF2 in mesothelioma development. They also concluded that the gene can be involved in cancers other than the nervous system tumors typical of the NF2 disorder.
• Limitations the authors state:
  • For cell line 222, the authors could not rule out that the altered message was caused by a mutation in a part of the gene they did not analyze.
  • For cell line 1-53, primary tumor DNA was not available, so genomic DNA from the cell line was analyzed instead.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Pleura, Tumor Suppressor Gene, Interstitial, Merlin, Oncogenesis, Neoplasm, Mesoderm.

Related studies

• Analysis of the neurofibromatosis type 2 gene in different human tumors of neuroectodermal origin — L.R. De Vitis, A. Tedde, et al. (1996)
• p16/CDKN2 gene and p53 gene alterations in Japanese non-smoking female lung adenocarcinoma — Y. Takeshima, T. Nishisaka, et al. (1996)
• Primary peritoneal epithelioid mesothelioma of clear cell type with a novel VHL gene mutation: a case report — A. Smith-Hannah, R. Naous (2019)
• Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma — V. Panou, M. Gadiraju, et al. (2018)
• Novel LRRK2 mutations and other rare, non-BAP1-related candidate tumor predisposition gene variants in high-risk cancer families with mesothelioma and other tumors — M. Cheung, Y. Kadariya, et al. (2021)
• K-ras mutations in human adenocarcinoma of the lung: association with smoking and occupational exposure to asbestos — K. Husgafvel-Pursiainen, P. Hackman, et al. (1993)

Browse more research in Proceedings of the National Academy of Sciences of the United States of America, or return to medical research.