Overexpression of Transcription Intermediary Factor 1 (TIF1) Is Associated with Low Grade Gastric Adenocarcinomas and Is Independent of SMAD-4 Depletion in TGF Pathway Dysregulation
F Francis, C Hajdu, E Blochin, H Yee, L Chiriboga, P Lee, R Xu. New York University School of Medicine, New York, NY
Background: Transcription Intermediary Factor 1 gamma (TIF1) is a competitor of SMAD4 for binding to receptor SMADs downstream of TGF receptor activation. It has been shown that about 30-50% of gastric cancers show SMAD4 depletion; however, it is unknown whether abnormal expression of TIF1 may also contribute to dysregulation of TGF signaling pathway in gastric cancers.
Design: Forty-six consecutive gastric cancer resection specimens were retrieved from the NYU Medical Center pathology database. The type and degree of differentiation of cancer was determined by two independent pathologists. Four micron-thick paraffin-embedded tissue sections were cut and immunostained for TIF1, SMAD4 and TGFII receptor using a Ventana automated immunostainer. Staining intensities were graded as 1+ (baseline expression in normal epithelium), 2+ (moderate) or 3+ (high expression). Abnormal expression in more than 30% cancer cells was considered to be positive.
Results: TIF1 overexpression is seen in 27/46 (59%) of gastric cancers. It is more frequently associated with intestinal type of gastric adenocarcinoma (19/26; 73%) and with well and moderately differentiated cancers (22/30; 73%) than with diffuse type (3/11; 27%) or poorly differentiated gastric cancers (5/16; 31%). SMAD4 depletion is seen in 19 of 46 (40%) cases. In contrast to TIF1 overexpression, SMAD4 depletion is more commonly observed in poorly differentiated (69%) and diffuse type gastric cancers (73%) than in well and moderately differentiated (27%) or intestinal type (23%) cancers. TGF overexpression is seen in 32/46 gastric carcinomas (70%) and is more common in intestinal type (88%) and in well and moderately differentiated cancers (83%) than in diffuse type (36%) or poorly differentiated gastric cancers (44%). Sixty-eight percent of cases with increased TGF and TIF1 expression show unaffected SMAD4 levels (15/22) and 32% show depleted SMAD4 levels (7/22).
Conclusions: Overexpression of TIF1 parallels TGF2 overexpression in gastric cancers. In contrast to SMAD4 depletion, TIF1 is commonly associated with low grade and intestinal type cancers. There is no association between TIF1 overexpression and SMAD4 depletion in the majority of cases. These findings suggest that TIF1 overexpression may play an important role in development of low grade and/or intestinal type gastric cancer consequent to dysregulation of TGF signaling pathway.
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 102, Tuesday Afternoon