Candidate microRNA biomarkers of pancreatic ductal adenocarcinoma: meta-analysis, experimental validation and clinical significance

Abstract

Background: The diagnostic and prognostic value of microRNA (miRNA) expression aberrations in pancreatic ductal adenocarcinoma (PDAC) has been studied extensively in recent years. However, differences in measurement platforms and lab protocols as well as small sample sizes can render gene expression levels incomparable.

Methods: A comprehensive meta-review of published studies in PDAC that compared the miRNA expression profiles of PDAC tissues and paired neighbouring noncancerous pancreatic tissues was performed to determine candidate miRNA biomarkers for PDAC. Both a miRNA vote-counting strategy and a recently published Robust Rank Aggregation method were employed. In this review, a total of 538 tumour and 206 noncancerous control samples were included.

Results: We identified a statistically significant miRNA meta-signature of seven up- and three down-regulated miRNAs. The experimental validation results showed that the miRNA expression levels were in accordance with the meta-signature. The results from the vote-counting strategy were consistent with those from the Robust Rank Aggregation method. The experimental validation confirmed that the statistically unique profiles identified by the meta-review approach could discriminate PDAC tissues from paired nonmalignant pancreatic tissues. In a cohort of 70 patients, the high expression of miR-21 (p=0.018, HR=2.610; 95% CI=1.179-5.777) and miR-31 (p=0.039, HR=2.735; 95% CI=1.317-6.426), the low expression of miR-375 (p=0.022, HR=2.337; 95% CI=1.431-5.066) were associated with poor overall survival following resection, independent of clinical covariates.

Conclusions: The identified miRNAs may be used to develop a panel of diagnostic and prognostic biomarkers for PDAC with sufficient sensitivity and specificity for use in a clinical setting.

Figure 1

PRISMA 2009 flow chart. Only original experimental articles that were published in English and that analysed the differences in miRNA expression between PDAC tissue and noncancerous pancreatic tissue in humans were included. Articles were excluded if the studies did not use a miRNA microarray platform or if they profiled miRNAs in different histological subtypes.

Figure 2

Kaplan-Meier analysis of overall survival in patients with PDAC based on their expression of miR-155 (A), miR-100 (B), miR-21 (C), miR-221 (D), miR-31 (E), miR-143 (F), miR-23a (G), miR-217 (H), miR-148a (I) and miR-375 (J). p-values are based on the log-rank test.