Purpose

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Iris melanoma comprises 4% to 10% of all UMs and has a lower mortality rate. The genetic changes in iris melanoma are not as well characterized as ciliary body or choroidal melanoma. The aim of this study was to gain more insight into the genetic background of iris melanoma and iris nevi.

Design

Multicenter, retrospective case series.

Participants

Patients diagnosed with iris melanoma or iris nevi who underwent surgical intervention as primary or secondary treatment.

Methods

Next-generation sequencing of GNAQ, GNA11, EIF1AX, SF3B1, BAP1, NRAS, BRAF, PTEN, c-Kit, TP53, and TERT was performed on 30 iris melanomas and 7 iris nevi. Copy number status was detected using single nucleotide polymorphisms (SNPs) included in the next-generation sequencing (NGS) panel, SNP array, or fluorescent in situ hybridization. BAP1 immunohistochemistry was performed on all samples.

Main Outcome Measures

Mutation and copy number status were analyzed. Results of BAP1 immunohistochemistry were used for survival analysis.

Results

In 26 of the 30 iris melanoma and all iris nevi, at least 1 mutation was identified. Multiple mutations were detected in 23 iris melanoma and 5 nevi, as well as mutations in GNAQ and GNA11. Furthermore, 13 of 30 BAP1, 5 of 30 EIF1AX, and 2 of 30 SF3B1 mutations were identified in iris melanoma. No correlation between BAP1 status and disease-free survival was found. The iris nevi showed 1 EIF1AX and 3 BAP1 mutations. Two of the nevi, with a BAP1 mutation, were histologically borderline malignant. Mutations in NRAS, BRAF, PTEN, c-KIT, and TP53 were detected in 6 iris melanomas and 4 iris nevi.

Conclusions

Mutations that are often found in uveal and cutaneous melanoma were identified in this cohort of iris melanomas and iris nevi. Therefore, iris melanomas harbor a molecular profile comparable to both choroidal melanoma and cutaneous melanoma. These findings may offer adjuvant targeted therapies for iris melanoma. There was no prognostic significance of BAP1 expression as seen in choroidal melanoma. Consequently, iris melanoma is a distinct molecular subgroup of UM. Histologic borderline malignant iris nevi can harbor BAP1 mutations and may be designated iris melanocytic tumors of uncertain malignant potential.

中文翻译：

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虹膜黑素瘤和恶性潜力不确定的虹膜黑素细胞瘤的遗传背景

目的

葡萄膜黑色素瘤（UM）是成人中最常见的原发性眼内恶性肿瘤。虹膜黑色素瘤占所有UM的4％至10％，死亡率较低。虹膜黑色素瘤的遗传变化不如睫状体或脉络膜黑色素瘤为特征。本研究的目的是对虹膜黑色素瘤和虹膜痣的遗传背景有更多的了解。

设计

多中心回顾性案例系列。

参加者

被诊断为虹膜黑色素瘤或虹膜痣的患者接受外科手术作为主要或辅助治疗。

方法

对30例虹膜黑色素瘤和7例虹膜痣进行了GNAQ，GNA11，EIF1AX，SF3B1，BAP1，NRAS，BRAF，PTEN，c-Kit，TP53和TERT的下一代测序。使用下一代测序（NGS）面板，SNP阵列或荧光原位杂交中包含的单核苷酸多态性（SNP）检测拷贝数状态。对所有样品进行BAP1免疫组织化学。

主要观察指标

分析了突变和拷贝数状态。BAP1免疫组化的结果用于生存分析。

结果

在30个虹膜黑色素瘤和所有虹膜痣中，有26个至少鉴定出1个突变。在23个虹膜黑色素瘤和5个痣中检测到多个突变，以及在GNAQ和GNA11中检测到突变。此外，13的30 BAP1，30 5 EIF1AX，和2 30的SF3B1突变虹膜黑色素瘤进行了鉴定。没有发现BAP1状态与无病生存之间的相关性。虹膜痣显示1个EIF1AX和3个BAP1突变。从组织学角度来看，其中两个BAP1突变的痣是恶性的。在突变NRAS，BRAF，PTEN，C-KIT，和TP53 在6个虹膜黑色素瘤和4个虹膜痣中检出。

结论

在这一虹膜黑色素瘤和虹膜痣人群中，发现了葡萄膜和皮肤黑色素瘤中经常发现的突变。因此，虹膜黑色素瘤具有与脉络膜黑色素瘤和皮肤黑色素瘤可比的分子特征。这些发现可能为虹膜黑色素瘤提供辅助靶向治疗。脉络膜黑色素瘤中没有BAP1表达的预后意义。因此，虹膜黑色素瘤是UM的一个独特的分子亚群。组织学临界恶性虹膜痣可携带BAP1突变，可被确定为恶性潜能不确定的虹膜黑素细胞瘤。