Molecular Analysis of a Patient With Neurofibromatosis 2 (NF2) and Peritoneal Malignant Mesothelioma

Our plain-English summary of Molecular Analysis of a Patient With Neurofibromatosis 2 (NF2) and Peritoneal Malignant Mesothelioma, by C. Glass, L.M. Sholl, J.R. Landgraf, et al (The American Journal of Surgical Pathology, 2020).

The study

• Authors: C. Glass, L.M. Sholl, J.R. Landgraf, L. Chirieac, V.L. Roggli
• Journal: The American Journal of Surgical Pathology
• Published: 2020;44(2):288-292
• Type of article: Case report
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Neurofibromatosis type 2 (NF2), an inherited disorder associated with multiple inherited schwannomas, meningiomas and ependymomas is caused by an autosomal dominant, likely loss of function germline mutation of the NF2 gene. Interestingly, biallelic NF2 gene inactivation is one of the most common mutations associated with the development of malignant mesothelioma (MM), a highly fatal malignancy that arises in the pleura and less frequently in the pericardium, peritoneum, and tunica vaginalis. It has been proposed that NF2 patients could potentially be at increased risk of developing MM. However, patients with inherited NF2 rarely develop MM. To date, only 2 cases describing patients diagnosed with both have been reported in the literature. Here, we describe the third case and for the first time, also provide molecular evidence that a "second hit" involving a somatic mutation is likely required to trigger the development of MM in this rare cohort. In our patient diagnosed with NF2 at age 25 who developed an aggressive peritoneal MM 15 years later, we identified a germline NF2 mutation and somatic mutations including BAP1. Of clinical relevance, our case supports a germline NF2 mutation may not necessarily be more susceptible to develop mesothelioma without a "second hit" mutation.

In plain English

This case report described a 40-year-old woman who had been diagnosed at age 25 with neurofibromatosis type 2 (NF2), an inherited condition, and who later developed malignant peritoneal mesothelioma, biphasic variant. She had worked as a financial service representative without any known occupational exposures. Lung tissue was not sampled, so asbestos bodies could not be assessed. Her tumor was first diagnosed elsewhere as sarcomatoid carcinoma. After review at the authors' institution, the microscopic and staining features were judged diagnostic of mesothelioma. She died within 1 year of presenting with symptoms. Gene sequencing of the tumor found an NF2 mutation in 67% of 138 reads. The authors read this as consistent with an inherited (germline) mutation plus a second hit in the tumor. Other mutations included BAP1, which they judged unlikely to be inherited, and loss of both copies of PTEN. No blood was available to confirm which mutations were inherited. The authors noted that only 2 earlier cases of NF2 with mesothelioma had been reported. They concluded that a "second hit" mutation is likely necessary for mesothelioma to develop in NF2 patients.

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 report with tumor tissue examination, immunohistochemical staining and next-generation sequencing of tumor DNA
• Who was studied: One 40-year-old woman with NF2 (diagnosed at age 25), a former smoker of 20 years, who developed peritoneal mesothelioma; tissue was reviewed at Duke and sequenced at Brigham and Women's Hospital
• Exposure: No known occupational exposures were reported. She worked as a financial service representative. Asbestos bodies could not be assessed because lung tissue was not sampled.
• Main results:
  • The tumor was diagnosed as malignant (diffuse) peritoneal mesothelioma, biphasic variant, after an earlier outside diagnosis of sarcomatoid carcinoma
  • An NF2 c.1446+1G>A mutation was found in 67% of 138 reads in the tumor. The authors said this high fraction is consistent with a germline (inherited) event and a second hit in the tumor.
  • Other mutations previously identified in mesotheliomas were found in the tumor: BAP1 (in 23% of 77 reads), a 2-copy deletion of PTEN, and PBRM1 (in 20% of 75 reads), among others
  • The tumor mutational burden was 6.844, higher than 81% of mesotheliomas sequenced with this version of the test
  • Despite a family history of melanoma, the BAP1 variant fraction of 23% was judged much lower than expected for a germline (inherited) mutation
  • The patient died within 1 year of presenting with symptoms
• The authors' conclusion: The authors concluded that their findings provide direct evidence that a "second hit" with commonly known somatic mutations is likely necessary for mesothelioma to develop in NF2 patients
• Limitations the authors state:
  • No blood was available for sequencing, so inherited status was inferred from tumor data. Definitive germline-versus-somatic assessment would require sequencing of non-cancerous tissue.
  • Lung tissue was not sampled, so the presence or absence of asbestos bodies could not be evaluated
  • Detection of structural rearrangements was limited to selected portions of introns of only 60 genes

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Germline Mutation, Pleura, Pericardium, Peritoneum, Tunica Vaginalis, Somatic Mutation, BAP1.

Related studies

• Fluorescence in situ hybridization (FISH) provides estimates of minute and interstitial BAP1, CDKN2A, and NF2 gene deletions in peritoneal mesothelioma — S. Brich, F. Bozzi, et al. (2020)
• The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma — A.D. Singhi, A.M. Krasinskas, et al. (2016)
• Neurofibromatosis 2 and malignant mesothelioma — M.E. Baser, A. De Rienzo, et al. (2002)
• Loss of BAP1 expression is very rare in peritoneal and gynecologic serous adenocarcinomas and can be useful in the differential diagnosis with abdominal mesothelioma — J. Andrici, J. Jung, et al. (2016)
• A Tumor-Specific Neo-Antigen Caused by a Frameshift Mutation in BAP1 Is a Potential Personalized Biomarker in Malignant Peritoneal Mesothelioma — J. Lai, Z. Zhou, et al. (2016)
• Detecting germline BAP1 mutations in patients with peritoneal mesothelioma: benefits to patient and family members — M. Kittaneh, C. Berkelhammer (2018)

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