Abstract 2160: PTEN deletion is associated with metastatic disease and worse prognosis in pancreatic cancer

Abstract

Abstract Background: PTEN is a tumor suppressor gene encoding a phosphatase. PTEN inactivation is a frequent event in cancer, occurring through various genetic and epigenetic alterations. Here we investigate the role of PTEN alterations in the microenvironment of ductal pancreatic adenocarcinoma (PDAC). Methods: Presence of PTEN was investigated by immunohistochemistry and mRNA-in-situ-hybridization (mRNA-ISH) by using multi-punch tissue microarrays (TMAs)containing at least 4 punches per tumor, in a set of 120 well characterized PDACs with full clinicopathological information. Expression was assessed separately in tumor and stromal cells. Multiplex ligation-dependent probe amplification (MLPA) of DNA probes to identify loss of heterozygosity (LOH) of the PTEN gene was additionally performed in 61 cases. Results were correlated with clinicopathological features including survival of the patients. Results: Loss of PTEN protein (i.e. average immunohistochemical expression in <10% of the neoplastic cells across all tumor punches) was found in 62% of PDAC cases, mostly paralleled by the results of mRNA-ISH. In 22.2% of the cases PTEN protein and/or mRNA loss was additionally observed in the tumor stroma. Interestingly, protein loss in the stromal cells was associated with distant metastasis (p = 0.0045). MLPA identified PTEN LOH (all exons or only exon 1) in 51% of all examined cases and in 73.5% of the cases with PTEN protein/mRNA loss. The occurrence of PTEN LOH was slightly more frequent among cases with concomitant PTEN protein loss in tumor and stromal cells (80%). PTEN LOH as identified by MLPA was associated with higher tumor grade (p = 0.0412), vascular invasion (p = 0.0176), presence of distant metastases (p = 0.0082) and decreased overall survival (p = 0.0127). In 26.5% of the cases with PTEN protein/mRNA loss, no PTEN deletion could be found suggesting occurrence of other genetic changes or epigenetic mechanisms. Conclusion: PTEN LOH is a major cause of PTEN loss in PDAC and is associated with aggressive tumor characteristics and worse patient prognosis. This is intensified by concomitant PTEN loss in tumor and stromal cells. Citation Format: Martin Wartenberg, Irene Centeno, Inti Zlobec, Alessandro Lugli, Aurel Perren, Eva Karamitopoulou. PTEN deletion is associated with metastatic disease and worse prognosis in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2160. doi:10.1158/1538-7445.AM2015-2160