Loss of PTEN Expression Is Associated with Poor Prognosis in Patients with Intraductal Papillary Mucinous Neoplasms of the Pancreas

Abstract

Purpose Previously, we reported PIK3CA gene mutations in high-grade intraductal papillary mucinous neoplasms (IPMN). However, the contribution of phosphatidylinositol-3 kinase pathway (PI3K) dysregulation to pancreatic carcinogenesis is not fully understood and its prognostic value unknown. We investigated the dysregulation of the PI3K signaling pathway in IPMN and its clinical implication. Experimental Design Thirty-six IPMN specimens were examined by novel mutant-enriched methods for hot-spot mutations in the PIK3CA and AKT1 genes. PIK3CA and AKT1 gene amplifications and loss of heterozygosity (LOH) at the PTEN locus were also evaluated. Additionally, the expression levels of PDPK1/PDK1, PTEN and Ki67 were analyzed by immunohistochemistry. Results Three cases carrying the E17K mutation in the AKT1 gene and one case harboring the H1047R mutation in the PIK3CA gene were detected among the 36 cases. PDK1 was significantly overexpressed in the high-grade IPMN vs. low-grade IPMN (p = 0.034) and in pancreatic and intestinal-type of IPMN vs. gastric-type of IPMN (p = 0.020). Loss of PTEN expression was strongly associated with presence of invasive carcinoma and poor survival in these IPMN patients (p = 0.014). Conclusion This is the first report of AKT1 mutations in IPMN. Our data indicate that oncogenic activation of the PI3K pathway can contribute to the progression of IPMN, in particular loss of PTEN expression. This finding suggests the potential employment of PI3K pathway-targeted therapies for IPMN patients. The incorporation of PTEN expression status in making surgical decisions may also benefit IPMN patients and should warrant further investigation.

Growth hormone receptor inhibition decreases the growth and metastasis of pancreatic ductal adenocarcinoma

“…18 Here, we found that PTEN was highly activated upon GHR silencing in both PANC-1 and HPAC cells (Figures 5e and f). Activation of PTEN in GHR silenced cells efficiently enhances apoptosis and inhibits proliferation by suppressing the active status of PI3K/AKT and its intermediates.…”

Loss of Activin Receptor Type 1B Accelerates Development of Intraductal Papillary Mucinous Neoplasms in Mice With Activated KRAS

“…Previously we have reported that members of the oncogenic PI3K signaling pathway are commonly altered at genetic or expression level in human IPMNs 29, 30 . Consistent with this finding, we found that the downstream gene PDK1 (3-phosphoinositide-dependent protein kinase-1) was up-regulated in the high-grade IPMN lesions of the AKP mice by IHC (Figure S3A and B).…”

“…The details on these human IPMN specimens can be found in our previous publication 30 . The IHC were scored independently by two pathologists (H.E.R.…”

Genetics and biology of pancreatic ductal adenocarcinoma

“…Human PDAC genomic studies have revealed the presence of oncogenic mutations in components of the PI3K pathway, including activating mutations in the catalytic PI3K subunit (PIK3CA/p110α), mutations in the regulatory PI3K subunit (PIK3R1/p85α), amplification of the PI3K downstream effector AKT2, and deletion/loss of tumor suppressor PTEN, a major negative regulator of PI3K (Aguirre et al 2004;Schonleben et al 2006;Jaiswal et al 2009;Ying et al 2011;Witkiewicz et al 2015). Mutations in the PI3K pathway, including PIK3CA and AKT1, are relatively common in IPMN-associated PDAC and account for >10% of cases (Schonleben et al 2006;Garcia-Carracedo et al 2013). Interestingly, the prognosis of these IPMN patients is strongly associated with loss of PTEN expression (Garcia-Carracedo et al 2013).…”

“…Mutations in the PI3K pathway, including PIK3CA and AKT1, are relatively common in IPMN-associated PDAC and account for >10% of cases (Schonleben et al 2006;Garcia-Carracedo et al 2013). Interestingly, the prognosis of these IPMN patients is strongly associated with loss of PTEN expression (Garcia-Carracedo et al 2013). Although constitutively active Pik3ca can induce PDAC formation in a GEMM (Eser et al 2013), PIK3CA mutations in human PDAC are largely concurrent with oncogenic KRAS mutation, suggesting that PI3K activation cooperates with oncogenic KRAS during pancreatic tumor development (Witkiewicz et al 2015).…”