Abstract LB-70: Tackling a clinical challenge: Using microRNAs to differentiate between low-and high-risk Pancreatic Cysts .
Authors: Wey Jennifer Permuth , McCarthy Susan , Chen Y. Ann , Fisher Kate , Kasprzak Agnieszka , Lloyd Mark , Qu Xiaotao , Yeatman Timothy , Klapman Jason , Coppola Domenico , Malafa Mokenge 
Published: August 2014

Background: Intraductal papillary mucinous neoplasms (IPMNs) are cystic pancreatic cancer (PC) precursors that are increasingly being detected incidentally by cross-sectional imaging. IPMNs harbor potential for invasive malignancy depending on the degree of histologic dysplasia which ranges from low to high grade, yet the only way to determine disease severity is through surgical resection and histopathologic investigation. Mi(cro)RNAs, non-coding RNAs that regulate one-third of protein coding genes, are attractive candidate biomarkers of early pancreatic malignancy because they are detectable in tissue and blood in a stable form, making them amenable to reliable measurement, and they have been implicated in the development and progression of PC. The goal of our pilot project was to discover and characterize a miRNA signature that accurately differentiates between low-grade IPMNs that merit continued surveillance and high-grade IPMNs that warrant immediate surgical resection. Methods: In our discovery phase, we microdissected formalin-fixed paraffin-embedded tissue (FFPE) and isolated total RNA from 28 pathologically-confirmed IPMNs (9 low-grade and 19 high-grade) surgically resected at our institution between 1999 and 2011, and evaluated the expression of 378 mature miRNAs using high-throughput Taqman Low Density Arrays. After normalization using the endogenous control RNU44, a rank-sum test was performed to compare the expression between the two groups for each miRNA. Results: Using a false discovery rate of 10%, there were 13 differentially expressed miRNAs with statistical significance. The top candidates include miR-100 (P=1.6 x10−3), miR-99b and miR-99a (P=2.7 x10−3), miR-342-3p and miR-126 (P = 3.7 x10−3), and miR-130a (P = 3.7 x10−3). Several of these miRNAs were highlighted in a recent investigation of FFPE tissue and cyst fluid from patients with IPMNs and other pancreatic cysts, demonstrating consistency of findings. Furthermore, the expression level of the top candidate miRNAs was down-regulated in high-grade compared to low-grade IPMN tissue, in line with recent data supporting a role for these miRNAs as tumor suppressors and regulators of key genes that contribute to cell proliferation and invasion in pancreatic and other malignancies. Analysis is underway to evaluate the expression of the top candidate miRNAs in an independent set of high- and low-grade IPMN tissue specimens, and to correlate miRNA expression with other possible clinical predictors of malignant potential. Conclusions: Although preliminary, our findings suggest that miRNAs may serve as a diagnostic adjunct for stratifying patients with IPMNs for continued surveillance or surgical resection.

Citation Format: Jennifer Permuth Wey, Susan McCarthy, Y. Ann Chen, Kate Fisher, Agnieszka Kasprzak, Mark Lloyd, Xiaotao Qu, Timothy Yeatman, Jason Klapman, Domenico Coppola, Mokenge Malafa. Tackling a clinical challenge: Using microRNAs to differentiate between low-and high-risk Pancreatic Cysts . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-70. doi:10.1158/1538-7445.AM2013-LB-70