Driver Mutations in Uveal Melanoma: Associations With Gene Expression Profile and Patient Outcomes.
Driver Mutations in Uveal Melanoma: Associations With Gene Expression Profile and Patient Outcomes.
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DOI：
10.1001/jamaophthalmol.2016.0903
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发表时间：
2016-07-01
影响因子：
8.1
通讯作者：
Harbour JW
中科院分区：
文献类型：
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作者：
Decatur CL;Ong E;Garg N;Anbunathan H;Bowcock AM;Field MG;Harbour JW
在葡萄膜黑色素瘤（UM）中，已经描述了以下5个基因中的频繁突变：BAP 1、EIF1AX、GNA11、GNAQ和SF3B1。了解这些突变的预后意义可以促进它们在精准医学中的应用。确定UM中驱动突变、基因表达谱（GEP）分类、临床病理特征和患者结局之间的相关性。回顾性研究了1998年11月1日至2014年7月31日期间由单一眼部肿瘤学家进行眼球摘除术治疗的UM患者。记录临床病理特征、患者结局、GEP分类（1类或2类）和突变状态。研究队列包括81名参与者。他们的平均年龄为61.5岁，37%（30/81）为女性。81例患者中35例（43%）的GEP分类为1级，81例患者中42例（52%）为2级，81例患者中4例（5%）未知。在64例患者中有29例（45%）发现了BAP1突变，81例患者中有36例（44%）发现了GNAQ突变，81例患者中有36例（44%）发现了GNA11突变，81例患者中有19例（24%）发现了SF3B1突变，81例患者中有14例（17%）发现了EIF1AX突变。BAP 1中的16个突变和EIF1AX中的6个突变以前未在UM中报道。GNAQ和GNA11突变相互排斥。BAP1、SF3B1和EIF1AX突变几乎相互排斥。采用多元回归分析，BAP1基因突变与2类GEP和老年患者相关。EIF1AX突变与1类GEP和睫状体受累的缺失相关。SF3B1突变与患者年龄较小相关。GNAQ突变与睫状体受累的缺失和更大的最大基底直径相关。GNA11突变与任何分析的特征无关。使用考克斯比例风险模型，2级GEP是与转移（相对危险度，9.4; 95%CI，3.1 - 28.5）和黑色素瘤特异性死亡率（相对危险度，15.7; 95%CI，3.6 - 69.1）最强相关的预后因素（两者均P <0.001）。在排除GEP分类后，BAP1突变的存在是与转移（相对风险，10.6; 95%CI，3.4 - 33.5）和黑色素瘤特异性死亡率（相对风险，9.0; 95%CI，2.8 - 29.2）最强相关的因素（两者均P <0.001）。BAP1、SF3B1和EIF1AX突变在UM肿瘤进展期间以几乎相互排斥的方式发生，并与不同水平的转移风险相关。这些突变可能有价值的预后标志物在UM。
Frequent mutations have been described in the following 5 genes in uveal melanoma (UM): BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. Understanding the prognostic significance of these mutations could facilitate their use in precision medicine. To determine the associations between driver mutations, gene expression profile (GEP) classification, clinicopathologic features, and patient outcomes in UM. Retrospective study of patients with UM treated by enucleation by a single ocular oncologist between November 1, 1998, and July 31, 2014. Clinicopathologic features, patient outcomes, GEP classification (class 1 or class 2), and mutation status were recorded. The study cohort comprised 81 participants. Their mean age was 61.5 years, and 37% (30 of 81) were female. The GEP classification was class 1 in 35 of 81 (43%), class 2 in 42 of 81 (52%), and unknown in 4 of 81 (5%). BAP1 mutations were identified in 29 of 64 (45%), GNAQ mutations in 36 of 81 (44%), GNA11 mutations in 36 of 81 (44%), SF3B1 mutations in 19 of 81 (24%), and EIF1AX mutations in 14 of 81 (17%). Sixteen of the mutations in BAP1 and 6 of the mutations in EIF1AX were previously unreported in UM. GNAQ and GNA11 mutations were mutually exclusive. BAP1, SF3B1, and EIF1AX mutations were almost mutually exclusive with each other. Using multiple regression analysis, BAP1 mutations were associated with class 2 GEP and older patient. EIF1AX mutations were associated with class 1 GEP and the absence of ciliary body involvement. SF3B1 mutations were associated with younger patient age. GNAQ mutations were associated with the absence of ciliary body involvement and greater largest basal diameter. GNA11 mutations were not associated with any of the analyzed features. Using Cox proportional hazards modeling, class 2 GEP was the prognostic factor most strongly associated with metastasis (relative risk, 9.4; 95% CI, 3.1–28.5) and melanoma-specific mortality (relative risk, 15.7; 95% CI, 3.6–69.1) (P < .001 for both). After excluding GEP class, the presence of BAP1 mutations was the factor most strongly associated with metastasis (relative risk, 10.6; 95% CI, 3.4–33.5) and melanoma-specific mortality (relative risk, 9.0; 95% CI, 2.8–29.2) (P < .001 for both). BAP1, SF3B1, and EIF1AX mutations occur during UM tumor progression in an almost mutually exclusive manner and are associated with different levels of metastatic risk. These mutations may have value as prognostic markers in UM.