Saito Motonobu, Shiraishi Kouya, Matsumoto Kenji, Schetter Aaron J, Ogata-Kawata Hiroko, Tsuchiya Naoto, Kunitoh Hideo, Nokihara Hiroshi, Watanabe Shun-Ichi, Tsuta Koji, Kumamoto Kensuke, Takenoshita Seiichi, Yokota Jun, Harris Curtis C, Kohno Takashi
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
Clin Cancer Res. 2014 Sep 15;20(18):4784-93. doi: 10.1158/1078-0432.CCR-14-1096. Epub 2014 Aug 20.
To examine the clinical utility of intratumor microRNAs (miRNA) as a biomarker for predicting responses to platinum-based doublet chemotherapy in patients with recurring lung adenocarcinoma (LADC).
The expression of miRNAs was examined in LADC tissues surgically resected from patients treated with platinum-based doublet chemotherapy at the time of LADC recurrence. Microarray-based screening of 904 miRNAs followed by quantitative reverse transcription-PCR-based verification in 40 test cohort samples, including 16 (40.0%) responders, was performed to identify miRNAs that are differentially expressed in chemotherapy responders and nonresponders. Differential expression was confirmed in a validation cohort (n = 63 samples), including 18 (28.6%) responders. An miRNA signature that predicted responses to platinum-based doublet chemotherapy was identified and its accuracy was examined by principal component and support vector machine analyses. Genotype data for the TP53-Arg72Pro polymorphism, which is associated with responses to platinum-based doublet chemotherapy, were subsequently incorporated into the prediction analysis.
A signature comprising three miRNAs (miR1290, miR196b, and miR135a*) enabled the prediction of a chemotherapeutic response (rather than progression-free and overall survival) with high accuracy in both the test and validation cohorts (82.5% and 77.8%). Examination of the latter was performed using miRNAs extracted from archived formalin-fixed paraffin-embedded tissues. Combining this miRNA signature with the TP53-Arg72Pro polymorphism genotype marginally improved the predictive power.
The three-miRNA signature in surgically resected primary LADC tissues may by clinically useful for predicting responsiveness to platinum-based doublet chemotherapy in patients with LADC recurrence.
探讨肿瘤内微小RNA（miRNA）作为预测复发性肺腺癌（LADC）患者对铂类双联化疗反应的生物标志物的临床实用性。
在LADC复发时，对接受铂类双联化疗的患者手术切除的LADC组织中miRNA的表达进行检测。对904种miRNA进行基于微阵列的筛选，随后在40个测试队列样本（包括16名（40.0%）反应者）中进行基于定量逆转录PCR的验证，以鉴定在化疗反应者和无反应者中差异表达的miRNA。在包括18名（28.6%）反应者的验证队列（n = 63个样本）中确认了差异表达。鉴定出一种预测对铂类双联化疗反应的miRNA特征，并通过主成分分析和支持向量机分析检查其准确性。随后将与对铂类双联化疗反应相关的TP53-Arg72Pro多态性的基因型数据纳入预测分析。
由三种miRNA（miR1290、miR196b和miR135a*）组成的特征能够在测试队列和验证队列中以高精度预测化疗反应（而非无进展生存期和总生存期）（分别为82.5%和77.8%）。后者的检测使用从存档的福尔马林固定石蜡包埋组织中提取的miRNA进行。将这种miRNA特征与TP53-Arg72Pro多态性基因型相结合，略微提高了预测能力。
手术切除的原发性LADC组织中的三种miRNA特征在临床上可能有助于预测LADC复发患者对铂类双联化疗的反应性。
