Drahos Jennifer, Schwameis Katrin, Orzolek Linda D, Hao Haiping, Birner Peter, Taylor Phillip R, Pfeiffer Ruth M, Schoppmann Sebastian F, Cook Michael B
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DDHS, Bethesda, Maryland.
Department of Surgery, Upper-GI-Service, CCC-GET Unit, Medical University of Vienna, Vienna, Austria.
Cancer Epidemiol Biomarkers Prev. 2016 Mar;25(3):429-37. doi: 10.1158/1055-9965.EPI-15-0161. Epub 2015 Nov 24.
The tissue specificity and robustness of miRNAs may aid risk prediction in individuals diagnosed with Barrett's esophagus. As an initial step, we assessed whether miRNAs can positively distinguish esophageal adenocarcinoma from the precursor metaplasia Barrett's esophagus.
In a case-control study of 150 esophageal adenocarcinomas frequency matched to 148 Barrett's esophagus cases, we quantitated expression of 800 human miRNAs in formalin-fixed paraffin-embedded tissue RNA using NanoString miRNA v2. We tested differences in detection by case group using the χ(2) test and differences in expression using the Wilcoxon rank-sum test. Bonferroni-corrected statistical significance threshold was set at P < 6.25E-05. Sensitivity and specificity were assessed for the most significant miRNAs using 5-fold cross-validation.
We observed 46 distinct miRNAs significantly increased in esophageal adenocarcinoma compared with Barrett's esophagus, 35 of which remained when restricted to T1b and T2 malignancies. Three miRNAs (miR-663b, miR-421, and miR-502-5p) were detected in >80% esophageal adenocarcinoma, but <20% of Barrett's esophagus. Seven miRNAs (miR-4286, miR-630, miR-575, miR-494, miR-320e, miR-4488, and miR-4508) exhibited the most extreme differences in expression with >5-fold increases. Using 5-fold cross-validation, we repeated feature (miR) selection and case-control prediction and computed performance criteria. Each of the five folds selected the same top 10 miRNAs, which, together, provided 98% sensitivity and 95% specificity.
This study provides evidence that tissue miRNA profiles can discriminate esophageal adenocarcinoma from Barrett's esophagus. This large analysis has identified miRNAs that merit further investigation in relation to pathogenesis and diagnosis of esophageal adenocarcinoma.
These candidate miRNAs may provide a means for improved risk stratification and more cost-effective surveillance.
微小RNA（miRNA）的组织特异性和稳定性可能有助于对诊断为巴雷特食管的个体进行风险预测。作为第一步，我们评估了miRNA是否能够将食管腺癌与癌前化生的巴雷特食管进行阳性区分。
在一项病例对照研究中，150例食管腺癌与148例巴雷特食管病例进行频率匹配，我们使用NanoString miRNA v2定量分析福尔马林固定石蜡包埋组织RNA中800种人类miRNA的表达。我们使用χ²检验检测病例组在检测方面的差异，并使用Wilcoxon秩和检验检测表达差异。经Bonferroni校正的统计学显著性阈值设定为P < 6.25E - 05。使用5折交叉验证评估最显著miRNA的敏感性和特异性。
我们观察到与巴雷特食管相比，食管腺癌中有46种不同的miRNA显著增加，其中35种在局限于T1b和T2期恶性肿瘤时仍然存在。三种miRNA（miR - 663b、miR - 421和miR - 502 - 5p）在超过80%的食管腺癌中被检测到，但在不到20%的巴雷特食管中被检测到。七种miRNA（miR - 4286、miR - 630、miR - 575、miR - 494、miR - 320e、miR - 4488和miR - 4508）表现出最极端的表达差异，增加超过5倍。使用5折交叉验证，我们重复特征（miR）选择和病例对照预测并计算性能标准。五个折次中的每一个都选择了相同的前10种miRNA，它们共同提供了98%的敏感性和95%的特异性。
本研究提供了证据表明组织miRNA谱可以区分食管腺癌和巴雷特食管。这项大规模分析确定了与食管腺癌发病机制和诊断相关的值得进一步研究的miRNA。
这些候选miRNA可能为改善风险分层和更具成本效益的监测提供一种手段。
