Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients

Our plain-English summary of Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients, by C.M. Cebulla, E.M. Binkley, R. Pilarski, et al (Ophthalmic Genetics, 2015).

The study

• Authors: C.M. Cebulla, E.M. Binkley, R. Pilarski, J.B. Massengill, K. Rai, D.A. Liebner, M.J. Marino, A.D. Singh, M.H. Abdel-Rahman
• Journal: Ophthalmic Genetics
• Published: 2015;36(2):126-31
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: To evaluate the prevalence of BAP1 germline mutations in a series of young patients with uveal melanoma (UM), diagnosed before age 30.

Materials And Methods: The study was carried out on 14 young uveal melanoma patients (average age 21.4 years, range 3 months to 29 years). Germline DNA was extracted from peripheral blood. BAP1 sequencing was carried out using direct sequencing of all exons and adjacent intronic sequences. We also tested for germline mutations in additional melanoma-associated candidate genes CDKN2A and CDK4 (exon 4).

Results: We identified one patient with a pathogenic mutation (c. 1717delC, p.L573fs*3) in BAP1. This patient was diagnosed with UM at age 18 years and had a family history of a father with UM and a paternal grandfather with cancer of unknown origin. One additional patient had an intronic variant of uncertain significance (c.123-48T > G) in BAP1 while the remaining 12 patients had no alteration. None of the patients had CDKN2A or CDK4 (Exon 4) mutations. Family history was positive for a number of additional malignancies in this series, in particular for cutaneous melanoma, prostate, breast and colon cancers. There were no families with a history of mesothelioma or renal cell carcinoma.

Conclusions: This study suggests that a small subset of patients with early onset UM has germline mutation in BAP1. While young patients with UM should be screened for germline BAP1 mutations, our results suggest that there is a need to identify other candidate genes which are responsible for UM in young patients.

In plain English

This study looked for inherited (germline) mutations in the BAP1 gene in 14 patients diagnosed with uveal melanoma, an eye cancer, before age 30, at two ocular oncology centers in Ohio. Their average age was 21.4 years, ranging from 3 months to 29 years. Blood DNA was sequenced for BAP1 and for two other melanoma-related genes, CDKN2A and CDK4 (exon 4). The study did not examine asbestos exposure. One of the 14 patients (7.1%) had a harmful BAP1 mutation. That patient was diagnosed at age 18, had a father with uveal melanoma, and developed metastases to breast and bone at age 27. A second patient had a BAP1 variant of uncertain significance that the authors judged likely not harmful. No patient had CDKN2A or CDK4 exon 4 mutations. No family reported mesothelioma or renal cell carcinoma. The authors concluded that a small subset of young uveal melanoma patients carry germline BAP1 mutations and that other genes need to be identified. They noted that tumor characteristics were unavailable for several patients and that charts held little data on characteristic skin lesions for most patients.

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 case series: germline mutation screening of young patients with uveal melanoma from two ocular oncology centers
• Who was studied: 14 patients diagnosed with uveal melanoma before age 30 (average age 21.4 years, range 3 months to 29 years), from The Ohio State University and the Cleveland Clinic, accrued over 8 years
• Exposure: No asbestos exposure was studied. The study examined inherited (germline) mutations: direct sequencing of all exons and adjacent intronic sequences of BAP1, plus testing of CDKN2A and CDK4 (exon 4), using DNA from peripheral blood
• Main results:
  • One patient had a pathogenic BAP1 mutation (c. 1717delC, p.L573fs*3)
  • This was 1 of 14 patients (7.1%) with early onset uveal melanoma
  • The patient with the BAP1 mutation had a father with uveal melanoma and a paternal grandfather with cancer of unknown origin
  • The patient with the BAP1 mutation, treated with brachytherapy at age 18, developed biopsy-proven metastases to breast and bone at age 27
  • A second patient (FUM147) had an intronic BAP1 variant of uncertain significance. Splice-site prediction software suggested it is likely not pathogenic
  • No patient had CDKN2A or CDK4 (exon 4) mutations
  • Family history of mesothelioma and renal cell carcinoma was negative in all 14 patients
  • The most common cancers in relatives were prostate cancer (n = 6), breast cancer (n = 5), cutaneous melanoma (n = 5), colon cancer (n = 2) and lymphoma (n = 2)
• The authors' conclusion: The authors concluded that a small subset of patients with early onset uveal melanoma carry germline BAP1 mutations. They stated that young patients with uveal melanoma should be screened for these mutations, and that other genes responsible for uveal melanoma in young patients need to be identified.
• Limitations the authors state:
  • Tumor characteristics, including tumor size, were not available for several patients
  • For most patients, chart review contained little data on skin lesions characteristic of the BAP1 syndrome or on oculodermal melanocytosis
  • The pathology of a reported 'eye cancer' in one relative could not be confirmed

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Germline Mutation, CDKN2A, Colorectal Cancer, Mesothelioma, Carcinoma, BAP1 Tumor Predisposition Syndrome.

Related studies

• Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations — M.G. Zauderer, G. Jayakumaran, et al. (2019)
• CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma — M. Betti, A. Aspesi, et al. (2016)
• Germline BAP1-positive patients: the dilemmas of cancer surveillance and a proposed interdisciplinary consensus monitoring strategy — P. Star, A. Goodwin, et al. (2018)
• Well-differentiated papillary mesothelioma: clustering in a Portuguese family with a germline BAP1 mutation — C. Ribeiro, S. Campelos, et al. (2013)
• 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)
• Germline BAP1 mutations predispose to malignant mesothelioma — J.R. Testa, M. Cheung, et al. (2011)

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