Abstract
The burden of pancreatic cancer (PanC) requires innovation in the current diagnostic approach. This study aimed to uncover new circulating microRNAs (miRNAs) that would distinguish patients with PanC from healthy subjects (HS) compared with the cancer antigen 19-9 (CA 19-9), and predict patients' clinical phenotypes and outcomes. MiRNA expression profiles in plasma were investigated by using a two-stage process. In a discovery phase, miRNAs levels were analyzed using the GeneChip™ miRNA 4.0 Affymetrix assay in 10 pools of plasma samples from PanC patients and HS; in a validation phase, significantly altered miRNAs were re-tested in independent cohorts of cancer patients and controls by droplet digital PCR (ddPCR). The diagnostic performance of the resulting miRNAs was compared to CA 19-9 determinations, and the associations of miRNAs plasma levels with patients' clinical phenotypes and outcomes were also taken into account. Bioinformatics selection of miRNAs differentially expressed in plasma uncovered miR-18a-5p, miR-122-5p, miR-1273g-3p, and miR-6126 as candidate oncogenic miRNAs in PanC. The ddPCR technology confirmed the significant over-expression of miR-122-5p, miR-1273g-3p, and miR-6126 in PanC compared to HS, in line with the trend of the CA 19-9 levels. Plasma levels of miR-1273g-3p, in combination with CA 19-9, showed higher power in distinguishing PanC patients from HS compared to the CA 19-9 tested alone, with a gain in both sensitivity and negative predictive value indicating a low false-negative rate (SE = 90.2% and NPV = 92.3% vs. SE = 82.1% and NPV = 87.9%). None of the oncogenic miRNAs were able to distinguish between a neoplastic and a proliferative/inflammatory disease of the pancreas, and were not able to stratify subjects according to the clinical risk for the disease. The only valuable association in PanC patients was found between miR-1273g-3p and tumor stage, and increased miR-122-5p levels emerged as independent negative prognostic factor for PanC patients (HR = 1.58, 95% CI = 1.03–2.43, p = 0.037). Our data highlighted a role for circulating miR-1273g-3p and miR-122-5p as new diagnostic and prognostic biomarkers for PanC.
Highlights
Pancreatic cancer (PanC) is one of the most lethal forms of cancer [1]
If diabetes was ascertained within 2 years prior to enrollment into the study or to the pancreatic cancer (PanC) diagnosis, subjects were classified as early-onset diabetes; if diabetes was ascertained more than 2 years prior to enrollment into the study or to the PanC diagnosis, subjects were classified as late-onset diabetes
The principal component analysis (PCA) analysis revealed close proximity between healthy subjects (HS) with early-onset diabetes (Pool4) and PanC. According to this spatial distribution, miRNA expression levels in pools from PanC patients (Pools 6−7−8−9−10) were compared to those from HS (Pools 1−2−3−5): at the p < 0.01 significance threshold, 82 miRNAs appeared differently expressed in PanC patients compared to HS subjects, with 51 up- and 31 down-regulated
Summary
Pancreatic cancer (PanC) is one of the most lethal forms of cancer [1]. Risk factors for developing PanC include both genetics and environmental factors. Specific mutations in multiple genes have been found in roughly 10% of PanC patients, with varying penetrance and degree of the cancer risk for each of them [2]. Environmental risk factors include tobacco exposure, heavy alcohol intake, chronic pancreatitis, diet, obesity, cholecystectomy and/or gastric resection, Helicobacter Pylori infection, non-O blood groups, and type 1, 2, and 3 diabetes [3, 4]. The risk for diabetes-associated PanC has been reported to increase in patients with early-onset diabetes, and to decrease negatively along the years from the diabetes diagnosis [5, 6]
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