Downregulation of PTEN Expression in Intraductal Papillary Mucinous Neoplasm of the Pancreas Is Associated with an Invasive Phenotype
Hong D Xiao, Martha B Pitman, Mari Mino-Kenudson. Massachusetts General Hospital, Boston
Background: Tumor suppressor gene PTEN mutation is rare in pancreatic ductal adenocarcinomas (PDACs), but PTEN protein downregulation is seen in 70% of PDACs. It is hypothesized that PTEN downregulation facilitates activation of AKT, a downstream effector of KRAS. This hypothesis is especially relevant as 90% of PDACs harbor KRAS mutations. Intraductal papillary mucinous neoplasm (IPMN) is a precursor lesion to PDAC. Here we investigate PTEN expression as well as AKT activation and KRAS mutations in IPMN.
Design: Expression levels of PTEN (Cell Signaling) and phosphorated AKT (S473, Cell Signaling) are analyzed by immunohistochemistry on tissue microarrays consisting of multiple lesions from 43 IPMNs (mean age 67.2 yrs, M:F = 28:15) with matching non-neoplastic tissue. The 43 IPMNs consisted of 18 non-invasive IPMNs and 25 with an invasive component. In the invasive group, 15 cases harbored macroinvasion, and the remaining 10 cases contain only superficial invasion. The intraductal component was gastric-type in 12 cases, intestinal-type in 19, oncocytic-type in 6, pancreaticobiliary-type in 2 and mixed in 4. Immunostains were scored as 0 (negative), 1 (weak) and 2 (strong), as compared to the surrounding stroma. KRAS mutations were analyzed in 18 invasive cases by direct Sanger sequencing or by a PCR-based SNaPshot assay.
Results: Loss of PTEN expression (grade 0) was seen in only 5 of 43 (12%) IPMN cases, with strong or weak expression in the corresponding non-neoplastic glands. The frequency of PTEN loss was less than those reported in PDAC. All five cases contained an invasive component with four showing macroinvasion, suggesting an association of PTEN loss with an invasive phenotype (p<0.05). Three cases were of intestinal-type, and the remaining two cases were of oncocytic- or pancreaticobiliary-type. None of the 12 gastric-type IPMN showed PTEN loss. KRAS mutations were detected in 10 of 18 (56%) invasive IPMNs, similar to the reported frequencies in IPMN. Three of the 5 cases with PTEN loss harbored KRAS mutations. Strong pAKT expression (grade 2) was seen in 13 cases, 6 (46%) of which were invasive. Interestingly, none of the 5 cases with PTEN loss showed concomitant strong pAKT expression.
Conclusions: PTEN downregulation is less frequent in IPMN than reported in PDAC. PTEN loss appears to be associated with an invasive phenotype, suggesting that it may play a role in neoplastic progression of IPMN. However, PTEN loss is not associated with AKT activation nor KRAS mutations, suggesting an alternative PTEN signaling pathway involved.
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 265, Tuesday Morning