March 2012
Volume 53, Issue 14
ARVO Annual Meeting Abstract  |   March 2012
Bap1 Germline Mutation Co-segregating With Uveal Melanoma
Author Affiliations & Notes
  • David A. Maerker
    Ophthalmology, University of Regensburg, Regensburg, Germany
  • Micheal Zeschnigk
    Institut für Humangenetik, University of Duisburg Essen, Essen, Germany
  • Jasmin Nelles
    Institut für Humangenetik, University of Duisburg Essen, Essen, Germany
  • Herbert Jaegle
    Ophthalmology, University of Regensburg, Regensburg, Germany
  • Footnotes
    Commercial Relationships  David A. Maerker, None; Micheal Zeschnigk, None; Jasmin Nelles, None; Herbert Jaegle, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 3334. doi:
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      David A. Maerker, Micheal Zeschnigk, Jasmin Nelles, Herbert Jaegle; Bap1 Germline Mutation Co-segregating With Uveal Melanoma. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3334.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : Uveal melanoma is the most common primary cancer of the eye in adults and has a strong propensity for fatal metastasis. Familial uveal melanoma is a rare condition, comprising only ∼0,6% of all uveal melanoma patients. Based on chromosome 3 genotyping or global gene expression profiling two different classes of uveal melanomas can be defined. Loss of one chromosome 3 (monosomy 3) in the tumor is strongly associated with metastatic death of patients suggesting that inactivating mutations of a gene on the remaining chromosome 3 promotes metastasis.BAP1 which maps to 3p21 codes for an ubiquitin carboxy-terminal hydrolase interacting with the RING finger domain of the breast cancer 1, early onset protein (BRCA1). This gene is thought to be a tumor suppressor gene that functions in the BRCA1 growth control pathway. Lately BAP1 inactivating mutations were predominantly found in uveal melanomas with a high metastatic potential. We report a germline BAP1 mutation co-segregating with uveal melanoma in two family members.

Methods: : DNA was isolated from tumor tissue obtained from the affected mother and son. Chromosome 3 typing was performed by microsatellite analysis using 8 chromosome 3 markers. Sequence analysis of all BAP1 exons was performed on genomic DNA from tumors and mutations were confirmed in DNA from blood or normal tissue.

Results: : In 1998, the mother was diagnosed with uveal melanoma of the ciliary body at age 56. Since 1991 a tumor of the chamber angle was controlled. In 1997 the patient developed secondary glaucoma. Biopsy of the tumor resulted in diagnosis of an iris uveal melanoma with ciliary body involvement. The son was diagnosed with uveal melanoma in 2007 at age 45. He underwent proton radiation in 2008. In 2011 a recurrence of the uveal melanoma of the ciliary body occurred. The son further developed liver metastasis and was diagnosed with cutaneous melanoma in 2011, urothel carcinoma in 2010. There was no history of uveal melanoma or any other neoplasia (breast or ovarian cancer) in other family members. In both patients the tumor was finally treated by enucleation. In both tumors monosomy 3 and the same BAP1 missense mutation (L100P) was found by genotyping and sequence analysis, respectively. Subsequent BAP1 sequencing of the blood DNA confirmed the BAP1 germline mutation in both patients. Other family members did not undergo BAP1 sequencing.

Conclusions: : To our best knowledge this is the first report of BAP1 mutation in two family members affected by familial uveal melanoma. This strongly supports a role of BAP1 as tumor suppressor gene in uveal melanoma development.

Keywords: tumors • melanoma • uvea 

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