Germline BAP1 mutations predispose to malignant mesothelioma

Our plain-English summary of Germline BAP1 mutations predispose to malignant mesothelioma, by J.R. Testa, M. Cheung, J. Pei, et al (Nature Genetics, 2011).

The study

• Authors: J.R. Testa, M. Cheung, J. Pei, J.E. Below, Y. Tan, E. Sementino, N.J. Cox, A.U. Dogan, H.I. Pass, S. Trusa, M. Hesdorffer, M. Nasu, A. Powers, Z. Rivera, S. Comertpay, M. Tanji, G. Gaudino, H. Yang, M. Carbone
• Journal: Nature Genetics
• Published: 2011;43(10):1022-5
• Cited by: 814 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma, and because mesothelioma clustering is observed in some families, we searched for genetic predisposing factors. We discovered germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) in two families with a high incidence of mesothelioma, and we observed somatic alterations affecting BAP1 in familial mesotheliomas, indicating biallelic inactivation. In addition to mesothelioma, some BAP1 mutation carriers developed uveal melanoma. We also found germline BAP1 mutations in 2 of 26 sporadic mesotheliomas; both individuals with mutant BAP1 were previously diagnosed with uveal melanoma. We also observed somatic truncating BAP1 mutations and aberrant BAP1 expression in sporadic mesotheliomas without germline mutations. These results identify a BAP1-related cancer syndrome that is characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also be involved and that mesothelioma predominates upon asbestos exposure. These findings will help to identify individuals at high risk of mesothelioma who could be targeted for early intervention.

In plain English

This genetic study searched for inherited causes of mesothelioma in two US families with many cases, one in Wisconsin (family W) and one in Louisiana (family L). The authors reported no occupational asbestos or erionite exposure in these families. However, they found chrysotile asbestos in all five homes where affected family-L members had lived, and traces of tremolite and chrysotile in the home where affected family-W members were raised. In family W, six affected members (four with mesothelioma, two with breast or renal cancer) shared the same inherited mutation in the BAP1 gene. In family L, three people with mesothelioma and two with skin carcinomas shared a different BAP1 mutation. Some carriers also developed uveal melanoma, an eye cancer. Among 26 people with mesothelioma from outside these families, 2 carried inherited BAP1 mutations, and both had earlier been treated for uveal melanoma. None of the other 24 had uveal melanoma. The authors concluded that BAP1 mutations are associated with a new hereditary cancer syndrome. They suggested either that mesothelioma predominates when carriers are exposed to asbestos, or that the mutation alone may be enough to cause it.

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: Genetic study of two families with high mesothelioma incidence (linkage analysis, gene sequencing, tumor analyses), plus sequencing of BAP1 in a series of sporadic mesothelioma cases and laboratory tests on tumor cell lines
• Who was studied: Two US families with high mesothelioma incidence, one in Wisconsin (W) and one in Louisiana (L), whose members reportedly had no erionite or occupational asbestos exposure. Also 26 individuals with sporadic mesothelioma (germline DNA), with tumor DNA from 18 of them, and 12 mesothelioma cell lines.
• Exposure: No occupational asbestos exposure was evident in the families. Chrysotile asbestos was detected in the homes of family L, and traces of tremolite and chrysotile in the family W home. The 26 sporadic cases all reported asbestos exposure to their physicians, but this was not verified. The main factor studied was germline BAP1 gene mutation.
• Main results:
  • Family W: six affected members (four with mesothelioma, two with breast or renal cancer) carried identical germline BAP1 mutations; linkage analysis also indicated that a member with ovarian cancer was a carrier
  • Family L: three individuals with mesothelioma (one recently treated for uveal melanoma) and two with skin carcinomas carried a germline BAP1 mutation creating a stop codon
  • Some BAP1 mutation carriers in the families developed uveal melanoma in addition to mesothelioma
  • Mesotheliomas from the families showed additional tumor-level BAP1 alterations consistent with loss of both copies of the gene, and lacked BAP1 nuclear expression
  • Sporadic mesothelioma cases: 2 of 26 had germline BAP1 deletions. Both had been treated for uveal melanoma before their mesothelioma diagnosis (6 years and 1 year earlier). None of the remaining 24 had uveal melanoma.
  • Sporadic mesothelioma tumors: truncating BAP1 mutations were found in 4 of 18 (22%) tumors with available DNA
  • 7 of 12 mesothelioma cell lines lacked BAP1 expression; restoring BAP1 markedly decreased colony-forming ability
• The authors' conclusion: The authors concluded that BAP1 mutations are associated with a new hereditary cancer syndrome predisposing to mesothelioma, uveal melanoma and possibly other cancers. They hypothesized that mesothelioma predominates when carriers are exposed to asbestos, and alternatively that BAP1 mutation alone may be sufficient to cause mesothelioma.
• Limitations the authors state:
  • Asbestos exposure reported by the 26 sporadic cases was not verified by lung content or mineralogical analysis
  • No biopsies of the uveal melanomas were available because they were treated by laser or radiation

Topics

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

Medical terms in this study, explained in our Lexicon: BAP1 Tumor Predisposition Syndrome, Malignant Mesothelioma, Mesothelioma, Germline Mutation, BAP1, Asbestos Exposure.

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