Plasma MicroRNAs as Novel Biomarkers for Patients with Intraductal Papillary Mucinous Neoplasms of the Pancreas

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal cancers world-wide, partly because methods are lacking to detect disease at an early, operable stage. Noninvasive PDAC precursors called intraductal papillary mucinous neoplasms (IPMNs) exist, and strategies are needed to aid in their proper diagnosis and management. Data support the importance of mi(cro)RNAs in the progression of IPMNs to malignancy, and we hypothesized that miRNAs may be shed from IPMN tissues and detected in blood. Our primary goals were to measure the abundance of miRNAs in archived pre-operative plasma from individuals with pathologically-confirmed IPMNs and healthy controls and discover plasma miRNAs that distinguish between IPMN patients and controls and between ‘malignant’ and ‘benign’ IPMNs. Using novel nCounter technology™ to evaluate 800 miRNAs, we showed that a 30-miRNA signature distinguished 42 IPMN cases from 24 controls (area underneath the curve (AUC)= 74.4 (95% CI:62.3-86.5, p=0.002). The signature contained novel miRNAs and miRNAs previously implicated in pancreatic carcinogenesis that had 2-4 fold higher expression in cases than controls. We also generated a 5-miRNA signature that discriminated between 21 malignant (high-grade dysplasia and invasive carcinoma) and 21 benign (low- and moderate-grade dysplasia) IPMNs (AUC=73.2 (95% CI: 57.6-73.2, p=0.005)), and showed that paired plasma and tissue samples from patients with IPMNs can have distinct miRNA expression profiles. This study suggests feasibility of using new cost-effective technology to develop a miRNA-based blood test to aid in pre-operative identification of malignant IPMNs that warrant resection while sparing individuals with benign IPMNs the morbidity associated with overtreatment.

Combining radiomic features with a miRNA classifier may improve prediction of malignant pathology for pancreatic intraductal papillary mucinous neoplasms

“…Thus, overlap exists for 38 of the study participants in the current report and our previous publication [14]; the prior article [14] dealt with the development of a miRNA classifier whereas in this manuscript we emphasize standard radiologic features and radiomic features as predictors of IPMN pathology with and without the miRNA classifier. CT images were obtained from Moffitt's GE Centricity Picture Archiving and Communication System (PACS).…”

A pilot study of radiologic measures of abdominal adiposity: weighty contributors to early pancreatic carcinogenesis worth evaluating?

“…External validation in a large, independent data set is warranted. Furthermore, with a larger sample size, multivariable modeling and receiver characteristic curve analyses will be helpful to determine the utility of gender-specific radiologic measures of abdominal obesity in discriminating malignant from benign IPMNs, independent of and in combination with novel molecular and radiologic markers 19,20 , standard clinical and radiologic features encompassed by consensus guidelines 12 , and BMI. …”

“…However, consensus guidelines 12 incorrectly predict pathology in 30%–70% of cases 12,14-18 , causing under- and over-treatment. Thus, rationale exists for identifying noninvasive markers to improve diagnostic accuracy for IPMNs, especially those without high risk stigmata 19,20 . …”

The circulating miRNAs as diagnostic and prognostic markers

“…Ren and Yu, this year summarized in a review paper, the main miRNAs isolated from the serum or plasma and pancreatic juices with a potential role not only in the diagnosis of pancreatic cancer, but also in the prognosis and chemoresistance [167]. In particular, miR-21, 155,196 and miR-210 are demonstrated to be consistently deregulated in pancreatic patients [168]. miR-192, also showed higher expression levels in blood samples from pancreatic cancer patients, exhibiting high sensitivity (76%) and specificity (55%) [169].…”