Overview of BAP1 cancer predisposition syndrome and the relationship to uveal melanoma

Our plain-English summary of Overview of BAP1 cancer predisposition syndrome and the relationship to uveal melanoma, by B. Masoomian, J.A. Shields, C.L. Shields (Journal of Current Ophthalmology, 2018).

The study

• Authors: B. Masoomian, J.A. Shields, C.L. Shields
• Journal: Journal of Current Ophthalmology
• Published: 2018;30(2):102-109
• Type of article: Review
• Cited by: 83 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: The aim of this study was to review the genetics, epidemiology, clinical findings, and management of BRCA1-associated protein-1 (BAP1) cancer predisposition syndrome, particularly focusing on the development of uveal melanoma (UM).

Methods: This is a review article based on eligible studies identified by systematically searching PubMed, Web of Science, and reference lists.

Results: UM is the most common primary intraocular malignancy. Most UM cases are sporadic, but a small percentage has been documented with familial tendency. Until recently, there was little information regarding the genetics of this malignant tumor, and we have now begun to understand the pathways of development. BAP1 is a scavenger protein that regulates cell cycle, cellular differentiation, and DNA damage response. Patients and families with germline BAP1 mutation are predisposed to familial cancers including UM, mesothelioma, cutaneous melanoma (CM), renal cell carcinoma (RCC), and others. Clinicians should be aware of the implications of germline BAP1 mutation and advise genetic testing and assessment for BAP1 germline mutation in suspected patients and families.

Conclusions: The ability of BAP1 gene mutation to cause multiple tumor types and high penetrance in carriers suggests that this gene has an important role for influencing cancer cell growth. With progress in understanding the molecular landscape of UM and the development of treatments targeted to the pathways involving BAP1 and other gene mutations, it is possible to improve the outcome of this malignant cancer.

In plain English

This was a review of published research on BAP1 tumor predisposition syndrome, an inherited condition caused by a germline (inborn) BAP1 gene mutation. It focused on uveal melanoma, an eye cancer. The authors searched PubMed, Web of Science and reference lists. They studied no new patients; the findings they reported came from earlier studies. The review described carriers as predisposed to uveal melanoma, mesothelioma, skin melanoma and kidney cancer. It cited a report of 174 carriers in which 22% had mesothelioma. It reported that mesothelioma began earlier in carriers than in sporadic cases (median 55 vs 72 years), and that several reports found longer survival. It recounted how studies of two US families with much mesothelioma identified germline BAP1 mutation as their shared genetic change; the gene itself was identified in 1998. The article described these families as having "only minimal exposure to asbestosis", apparently meaning asbestos. It noted that mesothelioma in the western world is often associated with asbestos exposure. The authors said the evidence suggests an important role for this gene in cancer cell growth, and said clinicians should advise genetic testing for suspected patients and families.

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 of published studies (no new patients studied)
• Who was studied: Published studies on BAP1 cancer predisposition syndrome, especially in relation to uveal melanoma; the review's own search dates and number of included studies are not given
• Exposure: Germline (inherited) BAP1 gene mutation; asbestos is mentioned only as a background cause of mesothelioma in the western world
• Main results:
  • Cited study (Rai et al.): of 174 patients with germline BAP1 mutation, 130 (75%) developed at least one of five main tumors: uveal melanoma 31%, malignant mesothelioma 22%, MBAIT skin tumor 18%, cutaneous melanoma 13%, renal cell carcinoma 10%
  • Cited studies: mesothelioma was the second most common cancer in the syndrome; median age of onset in BAP1 carriers was 55 years vs 72 years for sporadic mesothelioma
  • Cited reports: patients with germline BAP1 mutation and mesothelioma showed sevenfold longer overall survival than those with sporadic mesothelioma; the review says survival 'may be' significantly longer
  • Cited history: in 3 small villages in Cappadocia, Turkey, 50% of all deaths were caused by mesothelioma, which pedigree studies found ran in some families in an autosomal dominant fashion
  • Cited history: the BAP1 enzyme itself was first identified in 1998
  • Cited history: two unrelated US families (L from Louisiana, W from Wisconsin) had a high incidence of mesothelioma. The article describes them as having 'only minimal exposure to asbestosis', apparently meaning asbestos. Two members of the L family developed uveal melanoma. Sequencing identified germline BAP1 as the mutated gene in both families.
  • Cited evidence: more than 80% of BAP1 gene carriers are ultimately affected by at least one type of cancer
  • Cited study: metastatic eye melanoma developed in 71% of the germline BAP1 mutation group vs 18% of controls
• The authors' conclusion: The authors wrote that the ability of BAP1 mutation to cause multiple tumor types, with high penetrance in carriers, suggests the gene has an important role in cancer cell growth. They said clinicians should advise genetic testing in suspected patients and families.
• Limitations the authors state:
  • The authors state that evidence-based management recommendations have not been established for these families
  • The authors state that the proportion of the syndrome caused by a new (de novo) mutation is unknown

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Epidemiology, BAP1 Tumor Predisposition Syndrome, Mesothelioma, Carcinoma, Germline Mutation.

Related studies

• BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs — M. Carbone, L.K. Ferris, et al. (2012)
• Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma — K.G. Ewens, E. Lalonde, et al. (2018)
• Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients — C.M. Cebulla, E.M. Binkley, et al. (2015)
• Dual Screen for Efficacy and Toxicity Identifies HDAC Inhibitor with Distinctive Activity Spectrum for BAP1-Mutant Uveal Melanoma — J.N. Kuznetsoff, D.A. Owens, et al. (2021)
• YAP Activity is Not Associated with Survival of Uveal Melanoma Patients and Cell Lines — Y.J. Kim, S.C. Lee, et al. (2020)
• Molecular characterization of melanoma cases in Denmark suspected of genetic predisposition — K.A. Wadt, L.G. Aoude, et al. (2015)

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