Mesothelioma: recent highlights

Our plain-English summary of Mesothelioma: recent highlights, by M. Carbone, H. Yang (Annals of Translational Medicine, 2017).

The study

• Authors: M. Carbone, H. Yang
• Journal: Annals of Translational Medicine
• Published: 2017;5(11):238
• Type of article: Review
• Cited by: 58 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Recent discoveries have elucidated some of the mechanisms responsible for the development of mesothelioma. These discoveries are: (I) the critical role of chronic inflammation in promoting mesothelioma growth, driven by the release of high mobility group box protein-1 (HMGB1) following asbestos deposition in tissues and its potential role as a biomarker to identify asbestos exposed individuals and mesothelioma patients; (II) the discovery that inherited heterozygous germline mutations of the deubiquitylase BRCA-associated protein 1 (BAP1) cause a high incidence of mesothelioma in some families; and that (III) germline BAP1 mutations lower the threshold of asbestos required to cause mesothelioma in mice, evidence of gene X environment interaction. These findings together with the identification of novel serum biomarkers, including HMGB1, Fibulin-3, etc., promise to revolutionize screening and treatment of this malignancy in the coming years.

In plain English

This is a review article. The authors summarized recent research on how mesothelioma develops, much of it from their own earlier studies. They described work showing that asbestos kills mesothelial cells in a way that releases a protein called HMGB1, which drives long-lasting inflammation. In an earlier study they described, a form of HMGB1 in the blood, at a cutoff of 2.00 ng/mL, told mesothelioma patients apart from asbestos-exposed individuals with 100% sensitivity and specificity. The authors noted that a clinical trial was to start in 2017 to check this. They reviewed findings that inherited BAP1 mutations caused a very high incidence of mesothelioma in some US families without occupational asbestos exposure. They also reviewed findings that mice carrying BAP1 mutations developed mesothelioma after very low asbestos doses that rarely caused it in normal mice. They described 52 mesothelioma cases from Zhejiang province, China, where the male-to-female ratio was 1:4 and the ratio of pleural to peritoneal cases was 1:3. The share of cases associated with asbestos was 7.1% (2/28) at one hospital and 75% (18/24) at another. The authors concluded that they were optimistic some mesotheliomas could be prevented and that HMGB1 or other biomarkers could be validated.

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: Review article, largely summarizing the authors' own earlier laboratory, animal and human studies
• Who was studied: No single study population. The review covers human cell studies, mouse and hamster experiments, families carrying BAP1 mutations, and mesothelioma cases from Eastern China, among others.
• Exposure: Asbestos in general (crocidolite is named in a cited South African miner study), erionite, SV40 virus, and inherited BAP1 mutations as a susceptibility factor
• Main results:
  • In the authors' earlier cell studies, asbestos caused death of human mesothelial cells that released HMGB1 into the space outside the cells.
  • In an earlier serum study, hyper-acetylated HMGB1 at a cutoff of 2.00 ng/mL distinguished mesothelioma patients from asbestos-exposed individuals with 100% sensitivity and specificity.
  • Inherited (germline) BAP1 truncating mutations caused a very high incidence of mesothelioma in some US families without occupational asbestos exposure.
  • Mice carrying germline BAP1 mutations developed mesothelioma after very low asbestos doses that rarely caused mesothelioma in normal (wild-type) mice.
  • BAP1 is mutated in over 60% of sporadic (non-inherited) mesotheliomas, making it the most commonly mutated gene in mesothelioma.
  • Among 52 mesothelioma cases in Zhejiang province, China, the male-to-female ratio was 1:4 (US: 4:1), the pleura-to-peritoneum ratio was 1:3 (US: 5:1), and the average age at diagnosis was 50 (US: 72).
  • In the same Chinese cases, 9 of 52 (17%) occurred in people aged 40 or younger, compared to less than 1% in that age group in the US.
  • In the Chinese cases, the association with asbestos was 38.4% overall: 7.1% (2/28) at Zhejiang Cancer Hospital and 75% (18/24) at Yuyao People's Hospital, which is near the center of the asbestos industry in Eastern China.
  • In the authors' earlier work, aspirin significantly inhibited mesothelioma growth in a xenograft model (human tumor cells grown in animals).
• The authors' conclusion: The authors were optimistic that, as the mechanisms of BAP1-related cancer are worked out, it will become possible to interfere with gene-environment interaction and prevent at least some mesotheliomas. They also hoped ongoing trials would validate HMGB1 and/or other biomarkers.
• Limitations the authors state:
  • The HMGB1 biomarker findings had not yet been validated; a clinical trial was to start in 2017 to do so.
  • Epidemiological data on SV40 and mesothelioma are not available; the support for a role of SV40 comes from mechanistic and animal experiments.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Chronic Inflammation, High Mobility Group Box 1 (HMGB1), Deposition, Biomarker, Discovery, Germline Mutation, BAP1.

Related studies

• Recent insights emerging from malignant mesothelioma genome sequencing — M. Carbone, G. Gaudino, et al. (2015)
• Proteome screening of pleural effusions identifies galectin 1 as a diagnostic biomarker and highlights several prognostic biomarkers for malignant mesothelioma — F. Mundt, H.J. Johansson, et al. (2014)
• Highlights of the 14th international mesothelioma interest group meeting: Pathologic separation of benign from malignant mesothelial proliferations and histologic/molecular analysis of malignant mesothelioma subtypes — A. Churg, K. Nabeshima, et al. (2018)
• The role of radiation treatment in pleural mesothelioma: Highlights of the 14th International Conference of the International mesothelioma interest group — R.M. MacRae, M. Ashton, et al. (2019)
• Asbestos and the lung: highlights of a detrimental relationship — M. Iliopoulou, C. Bostantzoglou, et al. (2017)
• Simian virus 40, poliovaccines and human tumors: a review of recent developments — M. Carbone, P. Rizzo, et al. (1997)

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