PRAME as an Independent Biomarker for Metastasis in Uveal Melanoma.
PRAME as an Independent Biomarker for Metastasis in Uveal Melanoma.
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DOI：
10.1158/1078-0432.ccr-15-2071
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发表时间：
2016-03-01
期刊：
影响因子：
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通讯作者：
Harbour JW
中科院分区：
文献类型：
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作者：
Field MG;Decatur CL;Kurtenbach S;Gezgin G;van der Velden PA;Jager MJ;Kozak KN;Harbour JW
葡萄膜黑色素瘤 (UM) 可通过基因表达谱 (GEP) 分为 1 类（低转移风险）和 2 类（高转移风险），后者与肿瘤抑制因子 BAP1 的突变失活密切相关。然而，一小部分 1 类肿瘤会引起转移性疾病。本研究的目的是鉴定 1 类肿瘤转移的生物标志物。使用前瞻性验证的 12 基因预后分类器，将 389 名连续 UM 患者分配为 1 类或 2 类。使用全局 GEP 和 SNP 微阵列对选定的肿瘤进行进一步分析。通过 qPCR 分析了 64 个 1 类肿瘤中的 PRAME mRNA 表达。在 1 类 UM 中，最重要的转移预测因子是 PRAME mRNA 表达 (P=0.0006)。 1 类 PRAME− 肿瘤的 5 年精算转移率为 0%，1 类 PRAME+ 肿瘤为 38%，2 类肿瘤为 71%。 1 类 PRAME+ 患者的中位无转移生存期为 88 个月，而 2 类患者为 32 个月。使用三个独立的数据集验证了研究结果，其中一个使用二体性 3 来识别低风险 UM。与 Class1PRAME+ 肿瘤相关的染色体拷贝数变化包括 1q、6p、8q 和 9q 的增加以及 6q 和 11q 的丢失。 PRAME 表达与较大的肿瘤直径（P=0.05）和 SF3B1 突变（P=0.003）相关。 PRAME 是 UM 的一种独立预后生物标志物，可识别 1 类或二体性肿瘤患者转移风险增加。这一发现可能会进一步提高 UM 预后测试和精准医疗的准确性。
Uveal melanoma (UM) can be classified by gene expression profiling (GEP) into Class 1 (low metastatic risk) and Class 2 (high metastatic risk), the latter being strongly associated with mutational inactivation of the tumor suppressor BAP1. Nevertheless, a small percentage of Class 1 tumors give rise to metastatic disease. The purpose of this study was to identify biomarkers of metastasis in Class 1 tumors. 389 consecutive patients with UM were assigned to Class 1 or 2 using a prospectively validated 12-gene prognostic classifier. Selected tumors were further analyzed using global GEP and SNP microarrays. PRAME mRNA expression was analyzed in 64 Class 1 tumors by qPCR. Among Class 1 UMs, the most significant predictor of metastasis was PRAME mRNA expression (P=0.0006). The 5-year actuarial rate of metastasis was 0% for Class1PRAME−, 38% for Class1PRAME+, and 71% for Class 2 tumors. Median metastasis-free survival for Class1PRAME+ patients was 88 months, compared to 32 months for Class 2 patients. Findings were validated using three independent datasets, including one using disomy 3 to identify low-risk UM. Chromosome copy number changes associated with Class1PRAME+ tumors included gain of 1q, 6p, 8q, and 9q and loss of 6q and 11q. PRAME expression was associated with larger tumor diameter (P=0.05) and SF3B1 mutations (P=0.003). PRAME is an independent prognostic biomarker in UM that identifies increased metastatic risk in patients with Class 1 or disomy 3 tumors. This finding may further enhance the accuracy of prognostic testing and precision medicine for UM.