MicroRNA profiling predicts survival in anti-EGFR treated chemorefractory metastatic colorectal cancer patients with wild-type KRAS and BRAF
MicroRNA profiling predicts survival in anti-EGFR treated chemorefractory metastatic colorectal cancer patients with wild-type KRAS and BRAF
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DOI：
10.1016/j.cancergen.2012.08.003
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发表时间：
2012-11-01
期刊：
影响因子：
1.9
通讯作者：
Sarhadi, Virinder Kaur
中科院分区：
文献类型：
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作者：
Mosakhani, Neda;Lahti, Leo;Sarhadi, Virinder Kaur
抗EGFR单克隆抗体（anti-EGFRmAb）用于治疗转移性结直肠癌（mCRC），但KRAS/BRAF突变患者和近一半无突变的患者无法缓解。我们进行了microRNA（miRNA）分析，以找到预测抗EGFR mAb疗效的miRNA。在99例mCRC患者中，我们通过微阵列研究了33例接受野生型KRAS/BRAF和三线至六线抗EGFR mAb治疗的患者的原发性肿瘤的差异miRNA表达，伴/不伴伊立替康。我们通过考克斯比例风险回归模型测试了每种miRNA与总生存期（OS）的相关性。与疾病对照组相比，进行性疾病组出现显著的miR-31* 上调和miR-592下调。通过定量逆转录聚合酶链反应验证miR-31* 表达及其靶基因SLC 26 A3和ATN 1的下调。基于miRNA表达的患者聚类揭示了患者聚类之间OS的显著差异。let-7家族成员在OS较差的患者群中显示出显著上调。此外，在聚类分析和考克斯比例风险回归模型中，miR-140- 5 p上调和miR-1224- 5 p下调与OS较差显著相关。在携带野生型KRAS/BRAF的mCRC患者中，miRNA谱可以有效预测抗EGFR mAb治疗的获益。更大系列的患者对于这些miRNA作为预测/预后标志物的应用是必要的。
Anti-EGFR monoclonal antibodies (anti-EGFRmAb) serve in the treatment of metastatic colorectal cancer (mCRC), but patients with a mutation in KRAS/BRAF and nearly one-half of those without the mutation fail to respond. We performed microRNA (miRNA) analysis to find miRNAs predicting anti-EGFRmAb efficacy. Of the 99 mCRC patients, we studied differential miRNA expression by microarrays from primary tumors of 33 patients who had wild-type KRAS/BRAF and third- to sixth-line anti-EGFRmAb treatment, with/without irinotecan. We tested the association of each miRNA with overall survival (OS) by the Cox proportional hazards regression model. Significant miR-31* up-regulation and miR-592 down-regulation appeared in progressive disease versus disease control. miR-31* expression and down-regulation of its target genes SLC26A3 and ATN1 were verified by quantitative reverse transcriptase polymerase chain reaction. Clustering of patients based on miRNA expression revealed a significant difference in OS between patient clusters. Members of the let-7 family showed significant up-regulation in the patient cluster with poor OS. Additionally, miR-140-5p up-regulation and miR-1224-5p down-regulation were significantly associated with poor OS in both cluster analysis and the Cox proportional hazards regression model. In mCRC patients with wild-type KRAS/BRAF, miRNA profiling can efficiently predict the benefits of anti-EGFRmAb treatment. Larger series of patients are necessary for application of these miRNAs as predictive/prognostic markers.