Prognostic significance of Wnt signaling pathway molecules in nongastric GIST patients: A tissue microarray-based (TMA) analysis.

Abstract

10529 Background: Pathogenesis in GIST could be related to cancer stem cell hypothesis (highly chemo resistant, very uncommon complete responses, kit is stem cell marker) even though no stem cell component in GIST has been yet demonstrated. Wnt signaling regulates proliferation in some normal and cancer stem cells as it occurs with intestinal epithelium. We have explored the prognostic significance of several Wnt signaling pathway and related molecules. To investigate the prognostic significance of β-Catenin, CDC25A, ROR2, p53, CUL4A, AKT-p and VEGFR-3 by immunohistochemical (IHC) analysis in TMA specimens of 101 non-gastric GIST. Methods: Data of diagnostic, therapeutic and follow-up procedures stem from the GIST Registry of GEIS. Cytoplasmic and/or membrane staining was deemed positive for ROR-2, VEGFR-3 and p-AKT antibodies whereas nuclear staining was positive for β-Catenin, CDC25A, CUL4A and p53 antibodies. IHC positive cases were considered if they displayed staining in at least 10% of cells. Statistical analyses for correlation of protein expression with known prognostic variables (mitoses, size) were performed with Mann-Whitney U test. Results: A subset of 101 non-gastric localized GIST patients was selected (90 intestinal, 15 others: mainly rectum and omentum). The median age was 62 y with gender distribution of 59M/42F and the median of follow-up was 36 months. The positivity for each protein was distributed as follows: ROR-2 63%, p-AKT 55%, β-Catenin 53%, VEGFR-3 22%, CDC25A 20%, p53 8% and CUL4A 7%. A statistically significant correlation was found between mitoses and β-Catenin (median 5 if negative/ 10 if positive, p=0.028); VEGFR-3 (median 5 if negative/21 if positive, p=0.002); CUL4A (median 6 if negative/60 if positive, p= 0.027). Additionally, tumor size was statistically correlated with VEGFR-3 (median 7 if negative/11 if positive, p=0.007). Conclusions: VEGFR-3, β-Catenin and CUL4A are correlated with the highest proliferative non-gastric GIST. These findings deserve further analysis and lead to potential new molecular therapeutic targets in GIST. This study was partially granted by Buesa Grant of GEIS.