@article{d75af713b77c4906ba3780078813f46a,
title = "Intraocular Metastasis in Unilateral Multifocal Uveal Melanoma Without Melanocytosis or Germline BAP1 Mutations",
abstract = "Importance: There has been speculation on the pathogenesis of unilateral multifocal uveal melanoma, but there remains no convincing explanation. Genetic analysis suggests that unilateral multifocal uveal melanoma may represent intraocular metastasis with increased risk of systemic metastasis. Objective: To evaluate the pathogenesis of unilateral multifocal uveal melanoma. Design, Setting, and Participants: This clinical case series was conducted in tertiary academic ocular oncology referral centers and included patients with unilateral multifocal uveal melanoma. Main Outcomes and Measures: Gene expression and mutation profiling of tumor samples. Results: Four patients (all male; age range, 54-77 years) who were diagnosed with uveal melanoma were treated with plaque brachytherapy, and subsequently developed a second discrete uveal melanoma in the same eye were included. None demonstrated ocular or oculodermal melanocytosis. All 8 tumors available for analysis exhibited class 2 gene expression profiles. In all 4 cases, the initial and subsequent tumors were available for targeted DNA sequencing and identical driver mutations were present in both tumors. Data were collected from September 2015 to August 2018. Conclusions and Relevance: Unilateral multifocal uveal melanoma in the absence of ocular melanocytosis appears to occur preferentially in tumors with the class 2 gene expression profile and a BRCA1-associated protein 1 gene (BAP1) mutation. The presence of identical BAP1 mutations in multiple tumors in the same eye in the absence of a germline BAP1 mutation suggests intraocular metastasis rather than independent primary tumors. These findings indicate that the first site of metastasis can be within the eye itself and suggest that patients with unilateral multifocal uveal melanoma may be at increased risk of systemic metastasis.",
author = "Durante, {Michael A.} and Walter, {Scott D.} and Manuel Paez-Escamilla and Julian Tokarev and Decatur, {Christina L.} and Dubovy, {Sander R.} and Schefler, {Amy C.} and Harbour, {J. William}",
note = "Funding Information: Funding/Support: This work was supported by National Cancer Institute grants R01 CA125970 (Harbour), Research to Prevent Blindness Inc Senior Scientific Investigator Award (Dr Harbour), the University of Miami Miller School of Medicine Medical Scientist Training Program (Mr Durante), Sheila and David Fuente Graduate Program in Cancer Biology (Mr Durante), the Center for Computational Science Fellowship (Mr Durante), and a generous gift from Dr Mark J. Daily (Dr Harbour). Bascom Palmer Eye Institute also received funding from the National Institutes of Health (core grant P30EY014801) and a Research to Prevent Blindness unrestricted grant. Funding Information: Additional Contributions: We thank the patients who generously contributed samples for this research and acknowledge the support of the Center for Computational Science High Performance Computing Group of the University of Miami. Funding Information: paid consultant for Castle Biosciences, licensee of this intellectual property, and he receives royalties from its commercialization. Dr Harbour reported grants from National Institutes of Health/National Cancer Institute and Research to Prevent Blindness during the conduct of the study; personal fees from Aura Biosciences, Immunocore, and Array BioPharma outside the submitted work; and patents to US 9,809,856 and US 9,441,277, both issued, licensed, and with royalties paid. Dr Walter reported personal fees from Castle Biosciences, Allergan, and Genentech outside the submitted work. No other disclosures were reported. Publisher Copyright: {\textcopyright} 2019 American Medical Association. All rights reserved.",
year = "2019",
month = dec,
doi = "10.1001/jamaophthalmol.2019.3941",
language = "English (US)",
volume = "137",
pages = "1434--1439",
journal = "JAMA Ophthalmology",
issn = "2168-6165",
publisher = "American Medical Association",
number = "12",
}