Abstract 1215: Loss of PTEN expression predicts poor prognosis in patients with intraductal papillary mucinous neoplasms of the pancreas.

Abstract

Abstract Purpose: Previously we have reported PIK3CA gene mutations in high-grade intraductal papillary mucinous neoplasms (IPMNs). However, the contribution of phosphatidylinositol-3 kinase pathway (PI3K) deregulation to pancreatic carcinogenesis is not fully understood and its prognostic value unknown. Here we conducted a comprehensive examination of the PI3K signaling pathway to gain an understanding of the extent of its deregulation in IPMN and the potential impact on clinical outcomes. Experimental Design: Thirty-six IPMN specimens were evaluated for the E542K and E545K (exon 9), and H1047R (exon 20) hot-spot mutations in the PIK3CA gene and E17K mutation in the AKT1 gene using novel mutant-enriched sequencing methods. PIK3CA and AKT1 gene amplifications and PTEN loss of heterozygosity (LOH) were also investigated. In addition, the expression levels of 3-phosphoinositide dependent protein kinase-1 (PDPK1/PDK1), PTEN/MMAC phosphatase and Ki67 proliferation marker were analyzed by immunohistochemistry in the samples. Results: Derangements at genetic level of at least one member of the PI3K pathway was detected in 18 of the 36 (50 %). Three of the 36 (8.3 %) IPMN cases carried the E17K mutation in the AKT1 gene and one case carried the H1047R mutation in the PIK3CA gene. PDK1 was significantly overexpressed in the IPMC (15/17; 88 %) vs IPMN (5/19; 26 %) (p = 0.000) and in intestinal and pancreatic-type of IPMN than gastric-type of IPMN (p = 0.015). PDK1 overexpression was also associated with higher proliferation index by Ki67 staining (p = 0.044). Loss of PTEN expression strongly correlated to reduced survival in this group of IPMN patients (p = 0.014). Conclusion: This is the first study showing AKT1 activating mutation in this subtype of pancreatic cancer using a novel mutant-enriched method. Our data, when combined with previous reports, indicate that oncogenic activation of the PI3K pathway involving PIK3CA and AKT1 genes mutations or aberrant expression of its members, in particular loss of PTEN expression and overexpression of PDK1 is a frequent event and can contribute to the progression of IPMNs. This finding suggests the potential employment of target therapies aiming at the PI3K signaling pathway for IPMN patients. More importantly, the incorporation of PTEN expression status in making surgical decisions for IPMN patients may have significant clinical impacts and should warrant further investigations. Citation Format: Dario Garcia-Carracedo, Andrew T. Turk, Stuart Fine, Nathan Akhavan, Benjamin C. Tweel, Ramon E. Parsons, John A. Chabot, John D. Allendorf, Helen Remotti, Gloria H. Su. Loss of PTEN expression predicts poor prognosis in patients with intraductal papillary mucinous neoplasms of the pancreas. [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 1215. doi:10.1158/1538-7445.AM2013-1215