L18Long non-coding RNA HSAT II as a new biomarker for the identification of high risk intraductal papillary mucinous neoplasms (IPMNs)

Background: Satellite repeat RNAs HSAT II belongs to an heterogeneous group of non-coding transcripts, namely long non-coding RNAs. HSAT II transcripts, recently found in pancreatic ductal adenocarcinoma (PDAC), reflect global alterations in heterochromatin silencing and could potentially useful in tracking malignant progression in IPMNs. Methods: We retrospectively evaluated 37 patients (median age 69y, range: 43y-83y) with histological diagnosis of IPMN (2010-2013) obtained from Pathology Departments of Campus Bio-Medico University of Rome. 19 were associated with PDAC, 8 with biliary tract cancer, 2 with colloid adenocarcinoma, 1 with neuroendocrine tumor, 1 with ampullary adenocarcinoma (intestinal-histotype). In 6 cases, IPMN was not associated with invasive carcinoma. Patients were divided into: low (n = 15), moderate (n = 13) and severe grade dysplasia (n = 9) IPMN. For statistical analysis (Fischer exact test), moderate and severe grade dysplasia were grouped as high grade dysplasia. A semiquantitative evaluation of HSAT II status was performed using RNA in situ hybridization (QuantiGene ViewRNA Assays, Affymetrix). The sections underwent RNA-ISH were compared with consecutive section stained in H&E. HSAT II expression were classified in: score 0, no staining; score 1, faint staining; score 2, moderate staining and score 3, intense staining. Invasive neoplastic tissue was used as positive control while normal pancreatic duct epithelia as negative control. Results: Normal pancreatic ducts resulted negative for HSAT II expression. Significant positive correlation between grade of dysplasia and HSAT II expression was found. High HSAT II levels were identified in 20% (3/15) of low grade IPMN and in 86% (19/22) of high grade IPMN lesions (p < 0.001) (RR: 5.867; 95% CI: 1.989 to 17.31). The sensitivity and specificity of HSAT II expression for high grade IPMNs were 80% and 86%, respectively. Positive correlation between HSATII transcript level and association with PDAC was also found (p = 0.038). Conclusions: High HSAT II expression is strongly associated with malignant progression in IPMN acting as a totally new biomarker useful for the identification of high-risk disease.