Identification of microRNA Biomarkers of Response to Neoadjuvant Chemoradiotherapy in Esophageal Adenocarcinoma Using Next Generation Sequencing
Identification of microRNA Biomarkers of Response to Neoadjuvant Chemoradiotherapy in Esophageal Adenocarcinoma Using Next Generation Sequencing
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DOI：
10.1245/s10434-018-6626-z
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发表时间：
2018-09-01
影响因子：
3.7
通讯作者：
Hussey, Damian J.
中科院分区：
文献类型：
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作者：
Chiam, Karen;Mayne, George C.;Hussey, Damian J.
背景临床试验报告，在接受食管腺癌手术的患者中，新辅助放化疗可提高总生存率，生存率提高10-15%。MicroRNA（miRNAs）是一种小的非编码RNA，已知可指导癌症的行为，包括对治疗的反应。我们研究了miRNAs预测新辅助放化疗后预后的能力。在新辅助放化疗和食管切除术前，从食管腺癌中获得内镜活检。使用下一代测序测量活检中的miRNA水平，并与手术切除中的病理反应和随后的存活率进行比较。通过Lasso回归和留一交叉验证来鉴定预测病理反应的miRNA比率。使用Kaplan-Meier分析评估候选miRNA比率与无复发生存期之间的关联。进行考克斯回归和Harrell's C分析以评估miRNA的预测性能。发现预测对新辅助放化疗的病理反应的两种miRNA比率（miR-4521/miR-340- 5 p和miR-101- 3 p/miR-451 a）与无复发生存相关。在考克斯回归分析中，这两种miRNA比率的治疗前表达、治疗前肿瘤分化、治疗后AJCC组织病理学肿瘤消退分级和治疗后肿瘤清除/边缘是与生存相关的显著因素。两个比值与治疗前因素的多变量分析得出风险预测准确度为85%（Harrell's C），与AJCC治疗反应分级的预测准确度（77%）相当。使用下一代测序鉴定的miRNA比率生物标志物可用于预测食管腺癌患者新辅助放化疗和食管切除术后的无病生存期。
Background. Clinical trials report improved overall survival following neoadjuvant chemoradiotherapy in patients undergoing surgery for esophageal adenocarcinoma, with a 10-15% survival improvement. MicroRNAs (miRNAs) are small noncoding RNAs that are known to direct the behavior of cancers, including response to treatment. We investigated the ability of miRNAs to predict outcomes after neoadjuvant chemoradiotherapy.Methods. Endoscopic biopsies from esophageal adenocarcinomas were obtained before neoadjuvant chemoradiotherapy and esophagectomy. miRNA levels were measured in the biopsies using next generation sequencing and compared with pathological response in the surgical resection, and subsequent survival. miRNA ratios that predicted pathological response were identified by Lasso regression and leave-one-out crossvalidation. Association between miRNA ratio candidates and relapse-free survival was assessed using Kaplan-Meier analysis. Cox regression and Harrell's C analyses were performed to assess the predictive performance of the miRNAs.Results. Two miRNA ratios (miR-4521/miR-340-5p and miR-101-3p/miR-451 a) that predicted the pathological response to neoadjuvant chemoradiotherapy were found to be associated with relapse-free survival. Pretreatment expression of these two miRNA ratios, pretreatment tumor differentiation, posttreatment AJCC histopathological tumor regression grading, and posttreatment tumor clearance/margins were significant factors associated with survival in Cox regression analysis. Multivariate analysis of the two ratios together with pretherapy factors resulted in a risk prediction accuracy of 85% (Harrell's C), which was comparable with the prediction accuracy of the AJCC treatment response grading (77%).Conclusions. miRNA-ratio biomarkers identified using next generation sequencing can be used to predict disease free survival following neoadjuvant chemoradiotherapy and esophagectomy in patients with esophageal adenocarcinoma.