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

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...

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Bibliographic Details
Published in:Clinical cancer research 2013-12, Vol.19 (24), p.6830-6841
Main Authors: GARCIA-CARRACEDO, Dario, TURK, Andrew T, SU, Gloria H, FINE, Stuart A, AKHAVAN, Nathan, TWEEL, Benjamin C, PARSONS, Ramon, CHABOT, John A, ALLENDORF, John D, GENKINGER, Jeanine M, REMOTTI, Helen E
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Antineoplastic agents
Biological and medical sciences
Carcinoma, Pancreatic Ductal - genetics
Carcinoma, Pancreatic Ductal - pathology
Carcinoma, Papillary - genetics
Carcinoma, Papillary - pathology
Class I Phosphatidylinositol 3-Kinases
Female
Gastroenterology. Liver. Pancreas. Abdomen
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Male
Medical sciences
Middle Aged
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Mutation
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - pathology
Pharmacology. Drug treatments
Phosphatidylinositol 3-Kinases - biosynthesis
Prognosis
PTEN Phosphohydrolase - biosynthesis
PTEN Phosphohydrolase - genetics
Signal Transduction - genetics
Tumors
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Summary: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. Thirty-six IPMN specimens were examined by novel mutant-enriched sequencing methods for hot-spot mutations in the PIK3CA and AKT1 genes. PIK3CA and AKT1 gene amplifications and loss of heterozygosity at the PTEN locus were also evaluated. In addition, the expression levels of PDPK1/PDK1, PTEN, and Ki67 were analyzed by immunohistochemistry. 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 versus low-grade IPMN (P = 0.034) and in pancreatic and intestinal-type of IPMN versus 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). 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.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-13-0624