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
Differential expression of a number of miRNAs has previously been detected between normal ovaries and epithelial ovarian cancer (EOC). However, miRNA expression signatures have not been demonstrated between primary human ovarian surface epithelial (HOSE) cell, cystadenoma, low malignant potential (LMP) ovarian tumor and ovarian carcinoma as well as fallopian tube. Here, we performed miRNA profiling in normal primary OSE cells, normal fallopian tube and ovarian tumors, including 7 cystadnomas, 6 LMP and 49 ovarian carcinomas, as well as 15 ovarian cancer cell lines and 5 HIOSE cell lines. While deregulated dozen miRNAs were observed in different histological types of cysadenoma, LMP and ovarian carcinoma compared to primary OSE and fallopian tube, there are no significantly common changed miRNAs between serous adenoma and LMP, as well as between mucinous adenoma and LMP. However, 3 miRNAs were co-downregulated and 7 miRNAs were co-upregulated in serous LMP and carcinoma. When comparing mucinous LMP and carcinoma, only 3 miRNAs were co-deregulated. In addition, 3 and 6 miRNAs were co-deregulated in mucinous and serous adenoma and carcinoma, respectively. While miRNA expression patterns are distinct among four histological types of ovarian carcinoma examined, upregulation of miR-221/222 family was found to have significant poor prognosis value in serious carcinoma (p<0.05). These results support the notion that majority of ovarian carcinoma are derived neither from cystadenoma nor from LMP. Further cluster analysis suggests that the serious ovarian cancer may be derived from fallopian tube or/and OSE. Also our data suggest that commonly deregulated miRNAs between adenoma, LMP and carcinoma could serve as not only early markers but also initiation pathogenetic factors in this malignancy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2998.
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