Deep sequencing reveals microRNAs predictive of antiangiogenic drug response
Deep sequencing reveals microRNAs predictive of antiangiogenic drug response
复制标题
DOI：
10.1172/jci.insight.86051
复制
发表时间：
2016-07-07
期刊：
影响因子：
8
通讯作者：
Rodriguez-Antona, Cristina
中科院分区：
文献类型：
--
作者：
Garcia-Donas, Jesus;Beuselinck, Benoit;Rodriguez-Antona, Cristina
大多数转移性肾细胞癌（RCC）患者在一线治疗中接受酪氨酸激酶抑制剂（TKI）治疗;然而，一部分患者对这些抗血管生成药物难治。microRNA（miRNAs）是一种调控分子，被证明是癌症的精确生物标志物。在这里，我们通过对74例转移性透明细胞肾细胞癌病例进行深度测序，确定了在TKI治疗下预测疾病进展的miRNA。29种miRNA在TKI治疗进展患者的肿瘤中差异表达（P值为6 x 10（-9）至3 x 10（-3））。在一个独立系列中选择用于验证的6种miRNA中，最相关的关联对应于miR-1307- 3 p、miR-155- 5 p和miR-221- 3 p（P分别为4.6 x 10（-3）、6.5 x 10（-3）和3.4 x 10（-2））。此外，基于2种miRNA的分类器区分TKI治疗后疾病进展的个体（AUC = 0.75，95% CI，0.64-0.85; P = 1.3 x 10（-4）），其预测价值优于常用的临床病理学风险因素。我们还鉴定了与无进展生存期和总生存期显著相关的miRNAs（最高命中率分别为P = 6.8 x 10（-8）和7.8 x 10（-7）），7个与早期进展性疾病重叠。总之，据我们所知，这是第一个miRNome综合研究，证明了miRNA对TKI反应的预测价值，并提供了一组新的相关标志物，可以帮助合理化转移性RCC治疗。
The majority of metastatic renal cell carcinoma (RCC) patients are treated with tyrosine kinase inhibitors (TKI) in first-line treatment; however, a fraction are refractory to these antiangiogenic drugs. MicroRNAs (miRNAs) are regulatory molecules proven to be accurate biomarkers in cancer. Here, we identified miRNAs predictive of progressive disease under TKI treatment through deep sequencing of 74 metastatic clear cell RCC cases uniformly treated with these drugs. Twenty-nine miRNAs were differentially expressed in the tumors of patients who progressed under TKI therapy (P values from 6 x 10(-9) to 3 x 10(-3)). Among 6 miRNAs selected for validation in an independent series, the most relevant associations corresponded to miR-1307-3p, miR-155-5p, and miR-221-3p (P = 4.6 x 10(-3), 6.5 x 10(-3), and 3.4 x 10(-2), respectively). Furthermore, a 2 miRNA-based classifier discriminated individuals with progressive disease upon TKI treatment (AUC = 0.75, 95% CI, 0.64-0.85; P = 1.3 x 10(-4)) with better predictive value than clinicopathological risk factors commonly used. We also identified miRNAs significantly associated with progression-free survival and overall survival (P = 6.8 x 10(-8) and 7.8 x 10(-7) for top hits, respectively), and 7 overlapped with early progressive disease. In conclusion, this is the first miRNome comprehensive study, to our knowledge, that demonstrates a predictive value of miRNAs for TKI response and provides a new set of relevant markers that can help rationalize metastatic RCC treatment.