Germline BAP1 mutations predispose to malignant mesothelioma

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Abstract

Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma ¹, and because mesothelioma clustering is observed in some families ¹, we searched for genetic predisposing factors. We discovered germline mutations in BAP1 ( BRCA1-associated protein 1) in two families with a high incidence of mesothelioma. Somatic alterations affecting BAP1 were observed in familial mesotheliomas, indicating biallelic inactivation. Besides mesothelioma, some BAP1 mutation carriers developed uveal melanoma. Germline BAP1 mutations were also found in two of 26 sporadic mesotheliomas: both patients with mutant BAP1 were previously diagnosed with uveal melanoma. Truncating mutations and aberrant BAP1 expression were common in sporadic mesotheliomas without germline mutations. These results reveal a BAP1-related cancer syndrome 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 identify individuals at high risk of mesothelioma who could be targeted for early intervention.

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Most cited references 18

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BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression.

Y Sekido, N Tommerup, Alexander Ishov … (1998)

We have identified a novel protein, BAP1, which binds to the RING finger domain of the Breast/Ovarian Cancer Susceptibility Gene product, BRCA1. BAP1 is a nuclear-localized, ubiquitin carboxy-terminal hydrolase, suggesting that deubiquitinating enzymes may play a role in BRCA1 function. BAP1 binds to the wild-type BRCA1-RING finger, but not to germline mutants of the BRCA1-RING finger found in breast cancer kindreds. BAP1 and BRCA1 are temporally and spatially co-expressed during murine breast development and remodeling, and show overlapping patterns of subnuclear distribution. BAP1 resides on human chromosome 3p21.3; intragenic homozygous rearrangements and deletions of BAP1 have been found in lung carcinoma cell lines. BAP1 enhances BRCA1-mediated inhibition of breast cancer cell growth and is the first nuclear-localized ubiquitin carboxy-terminal hydrolase to be identified. BAP1 may be a new tumor suppressor gene which functions in the BRCA1 growth control pathway.

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Splicing in action: assessing disease causing sequence changes.

D Baralle, M Baralle (2005)

Variations in new splicing regulatory elements are difficult to identify exclusively by sequence inspection and may result in deleterious effects on precursor (pre) mRNA splicing. These mutations can result in either complete skipping of the exon, retention of the intron, or the introduction of a new splice site within an exon or intron. Sometimes mutations that do not disrupt or create a splice site activate pre-existing pseudo splice sites, consistent with the proposal that introns contain splicing inhibitory sequences. These variants can also affect the fine balance of isoforms produced by alternatively spliced exons and in consequence cause disease. Available genomic pathology data reveal that we are still partly ignorant of the basic mechanisms that underlie the pre-mRNA splicing process. The fact that human pathology can provide pointers to new modulatory elements of splicing should be exploited.

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BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization.

Karen Ventii, Narra S. Devi, Kenneth L Friedrich … (2008)

BRCA1-associated protein-1 (BAP1), a deubiquitinating enzyme of unknown cellular function, is mutated in breast and lung cancers. In this study, we have shown for the first time that BAP1 has tumor suppressor activity in vivo by showing that BAP1 can suppress tumorigenicity of lung cancer cells in athymic nude mice. We show that BAP1 fulfills another criterion of a genuine tumor suppressor because cancer-associated BAP1 mutants are deficient in deubiquitinating activity. We show for the first time that one of the two predicted nuclear targeting motifs is required for nuclear localization of BAP1 and that a truncation mutant found in a lung cancer cell line results in BAP1 that fails to localize to the nucleus. Furthermore, we show that deubiquitinating activity and nuclear localization are both required for BAP1-mediated tumor suppression in nude mice. We show that BAP1 exerts its tumor suppressor functions by affecting the cell cycle, speeding the progression through the G(1)-S checkpoint, and inducing cell death via a process that has characteristics of both apoptosis and necrosis. Surprisingly, BAP1-mediated growth suppression is independent of wild-type BRCA1. Because deubiquitinating enzymes are components of the ubiquitin proteasome system, this pathway has emerged as an important target for anticancer drugs. The identification of the deubiquitinating enzyme BAP1 as a tumor suppressor may lead to further understanding of how the ubiquitin proteasome system contributes to cancer and aid in the identification of new targets for cancer therapy.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 5 August 2011

Publication date (Electronic): 28 August 2011

Publication date PMC-release: 1 April 2012

Volume: 43

Issue: 10

Pages: 1022-1025

Affiliations

[1 ]Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA

[2 ]Department of Medicine, University of Chicago, Chicago, IL, USA

[3 ]Department of Human Genetics, University of Chicago, Chicago, IL, USA

[4 ]Earth Sciences Department, KFUPM, Dhahran, Saudi Arabia

[5 ]Department of Chemical and Biochemical Engineering, University of Iowa, Iowa City, IA, USA

[6 ]New York University, Langone Medical Center and Cancer Center, New York, NY, USA

[7 ]Mesothelioma Applied Research Foundation, Alexandria, VA, USA

[8 ]University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA

[9 ]Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, HI, USA

[10 ]Department of Pathology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI, USA

Author notes

[* ]Correspondence should be addressed to J.R.T.( joseph.testa@ 123456fccc.edu ) or M.Ca. ( mcarbone@ 123456cc.hawaii.edu ).

AUTHOR CONTRIBUTIONS

J.R.T. led the team at FCCC (M.Ch., J.P., Y.T., E.S.) that first identified and characterized the BAP1 mutations and genomic alterations in each of the two mesothelioma families, performed the splicing and functional assays, and discovered BAP1 mutations in sporadic tumors and cell lines. N.J.C. designed and directed the genetic linkage analyses studies performed by J.E.B. H.I.P. treated many of these patients and together with S.T. and M.H. provided the tumor samples, DNA, and clinical information. A.U.D. performed the mineralogical studies. M.Ca. conceived the project, assembled the families and the entire research group, diagnosed mesotheliomas, and led the team at UHCC (M.N, A.P, Z.R., S.C., M.T., G.G., H.Y.) that confirmed the mutations in the two mesothelioma families and discovered germline and somatic mutations in sporadic mesotheliomas. M.N. led the experimental work conducted by the UHCC team. J.R.T. and M.Ca. wrote the manuscript.

Article

Manuscript ID: nihpa314867

DOI: 10.1038/ng.912

PMC ID: 3184199

PubMed ID: 21874000

SO-VID: 0c7b7d04-6921-452a-89d3-366d8ee1b7bb

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History

Funding

Funded by: National Cancer Institute : NCI

Award ID: P30 CA006927-49 || CA

Funded by: National Cancer Institute : NCI

Award ID: P01 CA114047-05 || CA

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