A Pilot Study to Develop a Diagnostic Test for Pancreatic Ductal Adenocarcinoma Based on Differential Expression of Select miRNA in Plasma and Bile

Abstract

OBJECTIVES:Accurate peripheral markers for the diagnosis of pancreatic ductal adenocarcinoma (PDAC) are lacking. We measured the differential expression of select microRNAs (miRNAs) in plasma and bile among patients with PDAC, chronic pancreatitis (CP), and controls.METHODS:We identified patients (n=215) with treatment-naive PDAC (n=77), CP with bile/pancreatic duct pathology (n=67), and controls (n=71) who had been prospectively enrolled in a Pancreatobiliary Biorepository at the time of endoscopic retrograde cholangiopancreatography or endoscopic ultrasound. Controls were patients with choledocholithiasis but normal pancreata. The sample was separated into training (n=95) and validation (n=120) cohorts to establish and then test the performance of PDAC Signature Panels in diagnosing PDAC. The training cohort (n=95) included age-matched patients with PDAC, CP, and controls. Panels were derived from the differential expression of 10 candidate miRNAs in plasma or bile. We selected miRNAs having excellent accuracy for inclusion in regression models.RESULTS:Using the training cohort, we confirmed the differential expression of 9/10 miRNAs in plasma (miR-10b, -30c, -106b, -132, -155, -181a, -181b, -196a, and -212) and 7/10 in bile (excluding miR-21, -132, and -181b). Of these, five (miR-10b, -155, -106b, -30c, and -212) had excellent accuracy for distinguishing PDAC. In the training and validation cohorts, the sensitivity/specificity for a PDAC Panel derived from plasma was 95/100% and 100/100%, respectively; in bile, these were 96/100% and 100/100%.CONCLUSIONS:Increased expression of miRNA-10b, -155, and -106b in plasma appears highly accurate in diagnosing PDAC. Additional studies are needed to confirm this Panel and explore its value as a prognostic test.

Prospective validation of microRNA signatures for detecting pancreatic malignant transformation in endoscopic-ultrasound guided fine-needle aspiration biopsies

“…In agreement with the recent study by Cote et al [34], we observed increased expression of miRNA-155 in plasma from PDAC patients. However, circulating miR-21 and miR-155 had poor discriminatory ability for identifying malignant disease ( Figure 5), compared to EUS-FNA miR-21 and miR-155 ( Figure 3).…”

“…We used small nuclear RNA U6 as an endogenous control [35]. We did evaluate other published endogenous controls, such as miR-16 and miR-425-5p [34], but these exhibited greater inter-sample variability than U6.…”

Sequential Validation of Blood-Based Protein Biomarker Candidates for Early-Stage Pancreatic Cancer

“…Further validation of the three-marker panel in independent prediagnostic cohorts will be required to demonstrate utility for pancreatic cancer screening, leading to the development of an US Food and Drug Administration-approved test for targeted screening populations. Moreover, further improvement in marker performance may result from inclusion in the panel of additional marker types other than circulating proteins (15)(16)(17)(18)(19)(20)(21)(22)46) through critical testing of marker combinations. …”

“…As a result, there is substantial ongoing effort to identify additional serological biomarkers that complement CA19-9 for the detection of early-stage PDAC. Markers investigated include proteins (9)(10)(11)(12)(13)(14), metabolites (15)(16)(17), autoantibodies (18,19), miRNAs (20)(21)(22), markers with aberrant glycosylation (CA19-9 and Tn antigens) (6,23,24), and exosomes (25). In view of the wide array of potential biomarkers, there is a need for systematic evaluation of candidates using CA19-9 as an anchor marker given its established performance.…”

miRNA analysis in pancreatic cancer: the Dartmouth experience

“…In 2009, Wang et al [24] demonstrated that miR-21, miR-210, miR-155 and miR-196a were upregulated in plasma of patients with PDAC when compared to healthy controls. Recently, two sets of miRNAs were identified to accurately discriminate PDAC patients over the control: (set 1) miR-20a, miR-21, miR-24, miR-25, miR-99a, miR-185 and miR-191; and (set 2) miR-10b, miR-155, miR-106b, miR-30c and miR-212 [25,26], respectively. In fecal samples, expression levels of miR-181b and miR-210 were significantly higher in patients with PDAC compared with the normal group [27].…”