Perez-Carbonell L, Sinicrope F A, Alberts S R, Oberg A L, Balaguer F, Castells A, Boland C R, Goel A
Center for Gastrointestinal Research; Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute, Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA.
1] Division of Oncology, Mayo Clinic, Rochester, MN, USA [2] Division Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
Br J Cancer. 2015 Jun 30;113(1):83-90. doi: 10.1038/bjc.2015.168. Epub 2015 Jun 2.
Advances in early detection and treatment have improved outcomes in patients with colorectal cancer (CRC). However, there remains a need for robust prognostic and predictive biomarkers. We conducted a systematic discovery and validation of microRNA (miRNA) biomarkers in two clinical trial cohorts of CRC patients.
We performed an initial 'discovery' phase using Affymetrix miRNA expression arrays to profile stage III CRC patients with and without tumour recurrence (n=50 per group) at 3-years of follow-up. All patients received adjuvant 5-fluorouracil (5-FU) plus oxaliplatin, that is, FOLFOX, treatment. During 'validation', we analysed miRNAs using qRT-PCR in an independent cohort of 237 stage II-IV CRC patients treated with 5-FU-based chemotherapy, as well as in normal colonic mucosa from 20 healthy subjects. Association with disease recurrence, disease-free survival (DFS) and overall survival (OS) was examined using Cox proportional hazard models.
In the discovery cohort, miR-320e expression was significantly elevated in stage III colon cancers from patients with vs without recurrence (95% confidence interval (CI)=1.14-1.42; P<0.0001). These results were then independently validated in stage II and III tumours. Specifically, increased miR-320e expression was associated with poorer DFS (hazard ratio (HR)=1.65; 95% CI=1.27-2.13; P=0.0001) and OS (HR=1.78; 95% CI=1.31-2.41; P=0.0003) in stage III CRC patients.
In two clinical trial cohorts, a systematic biomarker discovery and validation approach identified miR-320e to be a novel prognostic biomarker that is associated with adverse clinical outcome in stage III CRC patients treated with 5-FU-based adjuvant chemotherapy. These findings have important implications for the personalised management of CRC patients.
早期检测和治疗方面的进展改善了结直肠癌（CRC）患者的预后。然而，仍需要强大的预后和预测生物标志物。我们在两个CRC患者临床试验队列中进行了microRNA（miRNA）生物标志物的系统发现和验证。
我们使用Affymetrix miRNA表达阵列进行了初始“发现”阶段，以分析III期CRC患者在随访3年时有无肿瘤复发的情况（每组n = 50）。所有患者均接受辅助5-氟尿嘧啶（5-FU）加奥沙利铂，即FOLFOX治疗。在“验证”阶段，我们使用qRT-PCR分析了237例接受基于5-FU化疗的II-IV期CRC患者独立队列中的miRNA，以及20名健康受试者的正常结肠黏膜中的miRNA。使用Cox比例风险模型检查与疾病复发、无病生存期（DFS）和总生存期（OS）的关联。
在发现队列中，复发患者与未复发患者的III期结肠癌中miR-320e表达显著升高（95%置信区间（CI）= 1.14 - 1.42；P < 0.0001）。然后在II期和III期肿瘤中对这些结果进行了独立验证。具体而言，III期CRC患者中miR-320e表达增加与较差的DFS（风险比（HR）= 1.65；95% CI = 1.27 - 2.13；P = 0.0001）和OS（HR = 1.78；95% CI = 1.31 - 2.41；P = 0.0003）相关。
在两个临床试验队列中，一种系统的生物标志物发现和验证方法确定miR-320e是一种新的预后生物标志物，与接受基于5-FU辅助化疗的III期CRC患者的不良临床结局相关。这些发现对CRC患者的个性化管理具有重要意义。
