PATH-06. Loss of PDE10A is associated with brain metastases and other adverse clinicopathologic features of gastrointestinal carcinoma

Abstract Phosphodiesterase 10A (PDE10A), located on cytoband 6q27, acts as a haploinsufficient tumor suppressor in glioblastoma, where its loss drives aggressive tumor behavior and is associated with a proneural-to-mesenchymal (PN-MES) shift. Leveraging bioinformatic analyses of The Cancer Genome Atlas (TCGA) pan-cancer dataset, we identified gastrointestinal carcinomas, specifically stomach adenocarcinoma and colon adenocarcinoma, as cancers where 6q27/PDE10A loss is prognostic. In both stomach adenocarcinoma and colon adenocarcinoma, PDE10A loss was associated with reduced overall survival (OS) and progression-free survival (PFS). Additionally, PDE10A loss correlated with increased lymphatic invasion and higher AJCC pathologic nodal stage in colon adenocarcinoma. In an independent institutional cohort, immunohistochemical analysis showed lower PDE10A expression in metastatic colon adenocarcinomas compared to primary tumors. Furthermore, PDE10A loss and decreased protein expression corresponded with an epithelial-to-mesenchymal transition (EMT) phenotype in both cohorts, consistent with the known PN-MES shift observed in glioblastoma. PDE10A immunohistochemical staining of 84 brain metastases from various primary sites confirmed that gastrointestinal carcinoma, along with breast carcinoma, show the lowest levels of PDE10A expression. Brain metastases from lung, kidney, and thyroid have intermediate PDE10A expression. By contrast, liver carcinoma metastatic to the brain displayed the highest amount of PDE10A expression. In summary, PDE10A loss in gastrointestinal carcinoma is associated with decreased OS and PFS, more frequent lymphatic invasion, higher pathologic nodal stage, an EMT phenotype, and metastatic disease.