The Landscape of Glycogen Synthase Kinase-3 Beta Genomic Alterations in Cancer

Glycogen synthase kinase-3b (GSK-3b), a serine/threonine kinase, has been implicated in the pathogenesis of many cancers, with involvement in cell-cycle regulation, apoptosis, and immune response. Small-molecule GSK-3b inhibitors are currently undergoing clinical investigation. Tumor sequencing has revealed genomic alterations in GSK-3b, yet an assessment of the genomic landscape in malignancies is lacking. This study assessed >100,000 tumors from two databases to analyze GSK-3b alterations. GSK-3b expression and immune cell infiltrate data were analyzed across cancer types, and programmed death-ligand 1 (PD-L1) expression was compared between GSK-3b-mutated and wild-type tumors. GSK-3b was mutated at a rate of 1%. The majority of mutated residues were in the kinase domain, with frequent mutations occurring in a GSK-3b substrate binding pocket. Uterine endometrioid carcinoma was the most commonly mutated (4%) tumor, and copy-number variations were most commonly observed in squamous histologies. Significant differences across cancer types for GSK-3b-mutated tumors were observed for B cells (P = 0.018), monocytes (P = 0.002), dendritic cells (P = 0.005), neutrophils (P = 0.0003), and endothelial cells (P = 0.014). GSK-3b mRNA expression was highest in melanoma. The frequency of PD-L1 expression was higher among GSK-3b-mutated tumors compared with wild type in colorectal cancer (P = 0.03), endometrial cancer (P = 0.05), melanoma (P = 0.02), ovarian carcinoma (P = 0.0001), and uterine sarcoma (P = 0.002). Overall, GSK-3b molecular alterations were detected in approximately 1% of solid tumors, tumors with GSK-3b mutations displayed a microenvironment with increased infiltration of B cells, and GSK-3b mutations were associated with increased PD-L1 expression in selected histologies. These results advance the understanding of GSK-3b complex signaling network interfacing with key pathways involved in carcinogenesis and immune response.