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Mrinali Patel, Margaret M DeAngelis, Anne Marie Lane, Katie Mayne, Evangelos S Gragoudas, Ivana K Kim; Clinical characteristics of uveal melanoma in patients with germline BAP1 mutations. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6443.
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BAP1 (BRCA1 associated protein 1/ubiquitin carboxy-terminal hydrolase), located on chromosome region 3p12, is thought to be a tumor suppressor with cell cycle regulation activity. Patients with aggressive uveal melanomas and metastatic uveal melanoma exhibit a high rate of BAP1 mutations in the primary tumor. More recently, germline mutations have been found in patients with uveal melanoma and are thought to be implicated in a cancer predisposition syndrome. To date, the role of germline BAP1 mutations on the uveal melanoma phenotype has not yet been characterized.
We sequenced the BAP1 gene from blood samples of 507 patients with uveal melanoma and correlated the genetic results to clinical characteristics in this cohort.
Germline BAP1 mutations were identified in 25/507 (4.9%) patients. Average age at the time of uveal melanoma diagnosis was similar in patients with (54.4 years) and without (58.5 years) BAP1 mutations (p = 0.366, t test). Positive history of other malignancies (16% and 21%, respectively) and family history of cancer (79% and 70%, respectively) were similar in patients with and without BAP1 mutations. Patients with germline BAP1 mutations presented with larger tumors (largest tumor diameter: 13.9 mm vs. 12.3 mm, p = 0.0289, t-test) and were more likely to exhibit ciliary body involvement (44% vs. 21%, p = 0.0141, Fisher's exact test). There was a trend towards more pigmented tumors in BAP1-mutation bearing patients (p = 0.0633, Mann-Whitney U test). Rates of iris involvement (8% vs. 2%, p = 0.1146, Fisher's exact test) and extrascleral extension (8% vs. 3%, p = 0.222, Fisher's exact test) were not significantly different between patients with and without germline BAP1 mutations. The rate of metastases was higher, though not statistically significant, in patients with germline BAP1 mutations (30% vs. 18%, p = 0.1655, Fisher's exact test).
Germline BAP1 mutations, though infrequent, are associated with known risk factors for metastasis, larger tumors and tumors with ciliary body involvement, suggesting that the mutation may correlate with a more aggressive phenotype.
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