Clinical Characteristics of Uveal Melanoma in Patients With Germline BAP1 Mutations
Clinical Characteristics of Uveal Melanoma in Patients With Germline BAP1 Mutations
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DOI：
10.1001/jamaophthalmol.2015.1119
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发表时间：
2015-08-01
影响因子：
8.1
通讯作者：
Kim, Ivana K.
中科院分区：
文献类型：
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作者：
Gupta, Mrinali P.;Lane, Anne Marie;Kim, Ivana K.
重要性BAP 1（BRCA 1相关蛋白1基因）的体细胞突变经常在葡萄膜黑色素瘤中发现。迄今为止，生殖系BAP 1突变在葡萄膜黑色素瘤中的作用尚未characterized.Objective葡萄膜黑色素瘤的临床表型与生殖系BAP 1 mutations.DESIGN，SETING，AND PARTICIPANTS的特点回顾性队列研究在学术眼科转诊中心507葡萄膜黑色素瘤患者同意收集血液样本。研究时间为1992年6月22日至2010年12月14日。主要结果和指标葡萄膜黑色素瘤的临床特征和转移的发展。结果在507例葡萄膜黑色素瘤患者中，25例（4.9%）患者出现18个BAP 1基因多态性，其中9个为新发现。计算分析预测8例患者（1.6%）的8个BAP 1突变可能导致BAP 1蛋白受损。这8个突变中有5个是新的。将这8例患者与482例未发现BAP 1多态性的患者进行比较。在单变量分析中，与对照受试者相比，具有生殖系BAP 1突变的患者表现出更大的肿瘤直径（平均值，15.9 vs 12.3 mm; P = .004）和更高的睫状体受累率（75.0% vs 21.6%，P = .002）和转移率（71.4% vs 18.0%，P = .003）。生殖系BAP 1突变患者的癌症家族史频率增加（100% vs 65.9%，P = 0.06），特别是皮肤黑色素瘤（62.5% vs 9.9%，P <0.001）和眼部黑色素瘤（25.0% vs 1.9%，P = 0.01）。在诊断时的年龄、性别、其他恶性肿瘤史、视力、肿瘤与视神经或中心凹的距离、虹膜受累、巩膜外侵犯或肿瘤色素沉着方面没有发现差异。生殖系BAP 1突变增加了转移的风险，与睫状体受累无关（P = 0.02）。生殖系BAP 1突变作为转移的独立危险因素接近显著性（P = 0.09）。结论和相关性这些数据表明生殖系BAP 1突变很少发生在葡萄膜黑色素瘤中，并且与较大的肿瘤和较高的睫状体受累率相关，这是转移的2个已知危险因素。
IMPORTANCE Somatic mutations in BAP1 (BRCA1-associated protein 1 gene) are frequently identified in uveal melanoma. To date, the role of germline BAP1 mutations in uveal melanoma has not been characterized.OBJECTIVE To characterize the clinical phenotype of uveal melanoma in patients with germline BAP1 mutations.DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study at an academic ophthalmology referral center among 507 patients with uveal melanoma who consented for collection of blood samples. The study dates were June 22, 1992, to December 14, 2010.MAIN OUTCOMES AND MEASURES Clinical characteristics of uveal melanoma and the development of metastases. BAP1 gene sequencing from blood samples of patients with uveal melanoma was correlated with clinical characteristics.RESULTS Of 507 blood samples analyzed, 25 patients (4.9%) exhibited 18 BAP1 polymorphisms, of which 9 were novel. Computational analyses predicted that 8 BAP1 mutations in 8 patients (1.6%) were likely to result in damaged BAP1 protein. Five of these 8 mutations were novel. These 8 patients were compared with 482 patients in whom no BAP1 polymorphisms were identified. In univariate analyses, patients with germline BAP1 mutations exhibited larger tumor diameters (mean, 15.9 vs 12.3 mm; P = .004) and higher rates of ciliary body involvement (75.0% vs 21.6%, P = .002) and metastases (71.4% vs 18.0%, P = .003) compared with control subjects. Patients with germline BAP1 mutations exhibited increased frequency of family history of cancer (100% vs 65.9%, P = .06), particularly cutaneous melanoma (62.5% vs 9.9%, P < .001) and ocular melanoma (25.0% vs 1.9%, P = .01). No differences were identified in age at diagnosis, sex, history of other malignant neoplasm, presenting visual acuity, distance of the tumor from the optic nerve or fovea, iris involvement, extrascleral extension, or tumor pigmentation. Germline BAP1 mutations increased risk of metastasis independent of ciliary body involvement (P = .02). Germline BAP1 mutation approached significance as an independent risk factor for metastasis (P = .09).CONCLUSIONS AND RELEVANCE These data suggest that germline BAP1 mutations occur infrequently in uveal melanoma and are associated with larger tumors and higher rates of ciliary body involvement, 2 known risk factors for metastasis.