Abstract
BackgroundOnly a subset of radically resected pancreatic ductal adenocarcinoma (PDAC) patients benefit from chemotherapy, and identification of prognostic factors is warranted. Recently miRNAs emerged as diagnostic biomarkers and innovative therapeutic targets, while high-throughput arrays are opening new opportunities to evaluate whether they can predict clinical outcome. The present study evaluated whether comprehensive miRNA expression profiling correlated with overall survival (OS) in resected PDAC patients.Methodology/Principal FindingsHigh-resolution miRNA profiles were obtained with the Toray's 3D-Gene™-miRNA-chip, detecting more than 1200 human miRNAs. RNA was successfully isolated from paraffin-embedded primary tumors of 19 out of 26 stage-pT3N1 homogeneously treated patients (adjuvant gemcitabine 1000 mg/m2/day, days-1/8/15, every 28days), carefully selected according to their outcome (OS<12 (N = 13) vs. OS>30 months (N = 6), i.e. short/long-OS). Highly stringent statistics included t-test, distance matrix with Spearman-ranked correlation, and iterative approaches. Unsupervised hierarchical analysis revealed that PDACs clustered according to their short/long-OS classification, while the feature selection algorithm RELIEF identified the top 4 discriminating miRNAs between the two groups. These miRNAs target more than 1500 transcripts, including 169 targeted by two or more. MiR-211 emerged as the best discriminating miRNA, with significantly higher expression in long- vs. short-OS patients. The expression of this miRNA was subsequently assessed by quantitative-PCR in an independent cohort of laser-microdissected PDACs from 60 resected patients treated with the same gemcitabine regimen. Patients with low miR-211 expression according to median value had a significantly shorter median OS (14.8, 95%CI = 13.1–16.5, vs. 25.7 months, 95%CI = 16.2–35.1, log-rank-P = 0.004). Multivariate analysis demonstrated that low miR-211 expression was an independent factor of poor prognosis (hazard ratio 2.3, P = 0.03) after adjusting for all the factors influencing outcome.Conclusions/SignificanceThrough comprehensive microarray analysis and PCR validation we identified miR-211 as a prognostic factor in resected PDAC. These results prompt further prospective studies and research on the biological role of miR-211 in PDAC.
Highlights
With a 5-year survival rate of less than 5%, pancreatic ductal adenocarcinoma (PDAC), including more than 90% of pancreatic cancers, is the most lethal among the major solid tumors [1]
A further group of 60 patients was used as a validation cohort, with median overall survival (OS) and disease-free survival (DFS) of 20.9 and 11.9 months, respectively (See Figure S3 for the Kaplan-Meier plots)
Unsupervised hierarchical analysis of the data from this array revealed that PDAC specimens clustered according to their short/long-OS classification
Summary
With a 5-year survival rate of less than 5%, pancreatic ductal adenocarcinoma (PDAC), including more than 90% of pancreatic cancers, is the most lethal among the major solid tumors [1]. The prognosis of patients after complete resection is poor, with 3-year disease-free survival (DFS) rate at. A subset of radically resected PDAC patients benefit from chemotherapy, and adjuvant treatments can have substantial toxicities [4]. A subset of radically resected pancreatic ductal adenocarcinoma (PDAC) patients benefit from chemotherapy, and identification of prognostic factors is warranted. MiRNAs emerged as diagnostic biomarkers and innovative therapeutic targets, while high-throughput arrays are opening new opportunities to evaluate whether they can predict clinical outcome. The present study evaluated whether comprehensive miRNA expression profiling correlated with overall survival (OS) in resected PDAC patients
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