Risk stratification of gastrointestinal stromal tumors by CtBP2 and CD44 analysis.

Abstract

48 Background: C-terminal binding protein 2 (CtBP2) is an oncogenic transcription factor that promotes cancer stem cell (CSC) growth and self-renewal, and controls pathways for tumor initiation, progression, and response to therapy. Expression of CtBP2 is linked to aggressive behavior in ovarian cancer, while genetic or pharmacologic targeting of CtBP2 disrupts CSC growth and self-renewal. CD44 is a cell surface marker that has been linked to CSC populations in many solid tumors, though data is conflicting on its role as tumor suppressor or oncogene. Gastrointestinal stromal tumors (GIST) is an increasingly common malignancy where risk stratification is essential for guiding post-surgical adjuvant therapy. We hypothesized that CtBP2 and CD44 staining would enhance risk stratification of GIST which currently relies on purely non-molecular clinicopathologic criteria. Methods: We identified 149 GIST cases from 1990 to 2016 in the Virginia Commonwealth University Medical Center pathology archive. Clinical data for 121 patients was available. The Armed Forces Institute of Pathology (AFIP) criteria (Miettinen's criteria) was used to risk stratify GISTs using the size, site, and mitotic index of the primary tumor. Immunohistochemistry for CtBP2 and CD44 was then performed on GIST samples with adequate tumor (86, CD44; 87, CtBP2). Stains were scored 0 (negative) to 3 (maximum) by two independent pathologists. Statistical analysis (χ2) correlating AFIP risk category with CD44 and CtBP2 staining was performed using PRISM6. Results: Moderate and high risk GISTs, based on AFIP criteria, significantly correlated with high CtBP2 expression (score = 3, p = 0.046) and low CD44 expression (score = 0-2, p = 0.034). Conclusions: CD44 and CtBP2 staining can be used to risk stratify GIST, and may enhance and complement current clinical risk stratification systems. Our data also suggests a potential tumor suppressive role of CD44 in GIST. Additionally, based on our findings, investigation of therapeutics that target CtBP2 in GISTs should be pursued.