An asbestos-exposed family with multiple cases of pleural malignant mesothelioma without inheritance of a predisposing BAP1 mutation

Our plain-English summary of An asbestos-exposed family with multiple cases of pleural malignant mesothelioma without inheritance of a predisposing BAP1 mutation, by M. Cheung, Y. Kadariya, J. Pei, et al (Cancer Genetics, 2015).

The study

• Authors: M. Cheung, Y. Kadariya, J. Pei, J. Talarchek, F. Facciolo, P. Visca, L. Righi, I. Cozzi, J.R. Testa, V. Ascoli
• Journal: Cancer Genetics
• Published: 2015;208(10):502-7
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

We report a family with domestic exposure to asbestos and diagnosis of multiple cancers, including eight pleural malignant mesotheliomas and several other lung or pleural tumors. DNA sequence analysis revealed no evidence for an inherited mutation of BAP1. Sequence analysis of other potentially relevant genes, including TP53, CDKN2A, and BARD1, also revealed no mutation. DNA microarray analysis of tissue from two mesotheliomas revealed multiple genomic imbalances, including consistent losses of overlapping segments in 2q, 6q, 9p, 14q, 15q, and 22q, but no losses of chromosome 3 harboring the BAP1 locus. However, the results of immunohistochemical analysis demonstrated loss of nuclear BAP1 staining in three of six mesotheliomas tested, suggesting that somatic alterations of BAP1 occurred in a subset of tumors from this family. Since mesothelioma could be confirmed in only a single generation, domestic exposure to asbestos may be the predominant cause of mesothelioma in this family. Given the existence of unspecified malignant pleural tumors and lung cancers in a prior generation, we discuss the possibility that some other tumor susceptibility or modifier gene(s) may contribute to the high incidence of mesothelioma in this family. Because the incidence of mesothelioma in this family is higher than that expected even in workers heavily exposed to asbestos, we conclude that both asbestos exposure and genetic factors have played a role in the high rate of mesothelioma and potentially other pleural or lung cancers seen in this family.

Copyright © 2015 Elsevier Inc. All rights reserved.

In plain English

This report described one Italian family with asbestos exposure at home. Eight members of one generation, six women and two men, developed pleural malignant mesothelioma between 1987 and 2012. The index patient's father was a brick-furnace worker with long exposure to asbestos at work who likely brought fibers home on his clothes. All seven of his children developed cancer, six of them mesothelioma. Crocidolite was found in one patient's lung tissue. All the patients had died and no blood samples were available, so the authors tested tumor tissue and pleural fluid. Sequencing of samples from four cases found no BAP1 point mutations, and one patient's pleural fluid showed no BAP1 deletions. They found no mutations in TP53, CDKN2A or BARD1 in the samples tested. Three of six tumors had lost nuclear BAP1 staining, which the authors suggested reflected changes arising within those tumors. Two women in the previous generation had pleural cancers highly suspected, but not confirmed, to be mesothelioma. The authors judged domestic asbestos exposure likely the predominant cause. They speculated that both asbestos and unknown genetic factors played a role.

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: Family case report with genetic and tissue analysis (sequencing, chromosome microarray, MLPA, immunohistochemistry) of one family
• Who was studied: One Italian extended family, followed since the index patient was identified in 1996. Between 1987 and 2012, six women (mean age 62) and two men (mean age 67) in generation III developed pleural malignant mesothelioma.
• Exposure: Domestic asbestos exposure. The index patient's father (II-4), a brick-furnace worker with long occupational exposure, likely brought asbestos fibers home on his clothes. Crocidolite, an elevated fiber burden and asbestos bodies were found in lung tissue of case III-5. Asbestos bodies were found in cases III-2 and III-17.
• Main results:
  • All seven children of the brick-furnace worker (II-4) developed one or more cancers in adulthood, six of them mesothelioma.
  • Lung tissue from case III-5 showed crocidolite, an elevated fiber burden and asbestos bodies.
  • Sanger sequencing of BAP1 in samples from four family members with mesothelioma (III-1, III-2, III-5, III-7) found no point mutations.
  • MLPA testing of the pleural effusion from case III-5, made up of mostly normal cells, found no deletions in BAP1.
  • CDKN2A sequencing in one case (III-5) found no mutation, only a common polymorphism (rs11515).
  • No TP53 mutations were found in tissue from four tumors from the family.
  • No BARD1 mutation was found in pleural fluid cells from case III-5.
  • Chromosome microarray analysis of two mesotheliomas found overlapping losses in 2q, 6q, 9p, 14q, 15q and 22q. It found no losses of chromosome 3, where BAP1 is located.
  • Three of six tumors tested (III-1, III-7, III-17) showed loss of nuclear BAP1 staining. Tumors from III-2, III-5 and III-6 showed nuclear staining.
  • The three patients with relatively long survival (III-1: 34 months, III-7: 50 months, III-17: 34 months from diagnosis) had negative nuclear BAP1 staining. The patients with positive staining survived 11, 9 and 7 months.
  • Mesothelioma was confirmed only in generation III. The authors stated that it did not appear to be transmitted from one generation to the next. They added that the other cancers in generation II, including two pleural cancers highly suspected but not confirmed to be mesothelioma, leave open the possibility of an inherited cancer susceptibility.
• The authors' conclusion: The authors concluded that an inherited BAP1 mutation did not appear to be involved, and that domestic asbestos exposure appeared likely to be the predominant cause. They speculated that both asbestos and genetic factors played a role in the high rate of mesothelioma and of pleural and lung cancers in this family.
• Limitations the authors state:
  • No blood samples were available, so the search for an inherited mutation used tumor tissue and pleural fluid. All patients had died and samples were very limited.
  • Sanger sequencing would not detect deletions of the BAP1 gene within tumors.
  • The two pleural cancers in the prior generation (II-3 and II-8) were highly suspected to be mesothelioma but were not confirmed.
  • For two mesothelioma patients (III-1 and III-4), no X-ray or CT images were available for review.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, BAP1, Germline Mutation, CDKN2A, Mesothelioma, Lung Cancer, Asbestos Exposure.

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• 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)
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• Tumours associated with BAP1 mutations — R. Murali, T. Wiesner, et al. (2013)

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