期刊
BRITISH JOURNAL OF CANCER
卷 113, 期 1, 页码 83-90出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2015.168
关键词
microRNAs; expression; colorectal cancer; 5-fluorouracil; prognosis; biomarker
类别
资金
- National Cancer Institute, National Institutes of Health [R01 CA72851, CA181572, CA184792]
- Baylor Research Institute
- National Cancer Institute [K05CA-142885, CA-25224]
- Fundacion Alfonso Martin Escudero, Spain
- NCCTG Biospecimen Resource [CA-114740]
- Alliance for Clinical Trials in Oncology [CA31946]
- Alliance Statistics and Data Center [CA33601]
- Charles A Sammons Cancer Center
Background: 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. Methods: 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. Results: 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. Conclusions: 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.
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