High Frequency of Overexpression of Transcriptional Intermediary Factor 1 Gamma (TIF1) in Pancreatic Ductal Adenocarcinoma and Its Precursor Lesions
CH Hajdu, E Blochin, L Zhang, F Francis, H Yee, L Chiriboga, P Lee, R Xu. New York University School of Medicine, New York, NY; Mount Sinai School of Medicine, New York, NY
Background: Approximately 50 % of pancreatic adenocarcinomas show deletion or inactivation of SMAD-4/DEPC-4, a member of Transforming Growth Factor (TGF-) family. We hypothesize that TIF1, recently identified as a novel cofactor of SMAD2/3, competitive to SMAD4, may have a similar role in pancreatic cancer development.
Design: Eleven cases of mucinous cystic neoplasm (MCN) with and without pancreatic intraepithelial neoplasia (PanIN), 12 cases of IPMN, 13 cases of PanIN lesions, and 15 cases of pancreatic duct adenocarcinoma (PDA) were randomly selected from the archival Surgical Pathology files of the NYU Langone Medical Center and Mount Sinai Medical Center and confirmed by H&E slide review. Four micron-thick, formalin-fixed and paraffin-embedded tissue sections were immunostained with monoclonal mouse or rabbit anit-TIF-1 and TGF- II receptor using Ventana automated stainer. The intensity of immunostains is defined as 1+ (baseline expression in normal ductal epithelium), 2+ (moderate) and 3+ (high). Abnormal expression in more than 30% cancer cells is considered to be positive.
Results: Compared to baseline expression in the nuclei of normal ductal epithelium, 11 of 11 (100%) cases of MCNs, 10 of 12 IPMNs (80%), and 15 of 15 PDAs (100%) show overexpression of TIF1. Interestingly TIF1 overexpression is not observed in any of the 10 cases of low-grade PanIN (grade I, gastric type) associated with MCNs, but is seen in 10 of 13 (77%) independent PanINs (mostly grade II and III). Overexpression of TGF- II receptor protein is present in 5 of 16 cases (31%) of MCN, 4 of 12 (30%) IPMN, and none of the low grade PanINs associated with MCNs. Downregulation of TGF- II receptor protein is seen in 2 of MCNs and none of the other lesions.
Conclusions: The high frequency of overexpression of TIF1 in pancreatic precancerous lesions and PDAs suggests that this protein may play a critical role in the early oncogenesis of pancreatic adenocarcinomas. Unlike SMAD4, TIF1 is overexpressed in a high frequency in all three precursor lesions of pancreatic cancer, which may potentially serve as a screening marker for early diagnosis.
Category: Liver & Pancreas
Wednesday, March 11, 2009 9:30 AM
Poster Session V # 228, Wednesday Morning