Prognostic Significance of Abnormal MTAP and p16 Expression in Gastrointestinal Stromal Tumors (GISTs)

Molecular alterations in the CDKN2A gene have been identified as a poor prognostic marker in a small subset of gastrointestinal stromal tumors (GISTs). Investigations into the potential utility of p16 protein loss by immunohistochemistry (IHC) as a surrogate marker of CDKN2A deletion have revealed contradictory findings in various cancers. Recently, high concordance of MTAP and CDKN2A codeletion has been identified, suggesting the potential use of MTAP as a surrogate marker for CDKN2A deletion in various other tumor types. Our objective was to investigate the prognostic significance of MTAP and p16 expression in GISTs, with the aim of shedding light on its potential in refining risk stratification and optimizing patient management. We assembled our institutional cohort of 225 surgically resected GISTs. MTAP and p16 immunohistochemical stains were performed on the tissue microarrays, and we recorded the cytoplasmic expression (for MTAP) or cytoplasmic/nuclear (for p16) as negative (loss), weak to moderate/heterogenous (wild type), or strong diffuse (overexpression). We found MTAP loss in 11 (5%) cases and overexpression in 40 (18%), while p16 overexpression was found in 5 (2%) cases and loss in 45 (21%). Overexpression as well as loss of MTAP and p16 expression correlated with the presence of epithelioid histology (either pure or mixed with a spindle cell component), higher grade and pT-stage, necrosis, higher NCCN risk groups, and widespread disease at presentation. Overexpression as well as loss of MTAP and p16 expression predicts shortened progression-free survival and is associated with various known poor prognostic clinicopathologic parameters.