The Landscape of Glycogen Synthase Kinase-3 Beta Genomic Alterations in Cancer
Brittany A Borden1, Yasmine Baca2, Joanne Xiu2
1The Warren Alpert Medical School of Brown University, Providence, Rhode Island.
Abstract:
Glycogen synthase kinase-3β (GSK-3β), 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-3β inhibitors are currently undergoing clinical investigation. Tumor sequencing has revealed genomic alterations in GSK-3β, yet an assessment of the genomic landscape in malignancies is lacking. This study assessed >100,000 tumors from two databases to analyze GSK-3β alterations. GSK-3β expression and immune cell infiltrate data were analyzed across cancer types, and programmed death-ligand 1 (PD-L1) expression was compared between GSK-3β-mutated and wild-type tumors. GSK-3β was mutated at a rate of 1%. The majority of mutated residues were in the kinase domain, with frequent mutations occurring in a GSK-3β 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-3β-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-3β mRNA expression was highest in melanoma. The frequency of PD-L1 expression was higher among GSK-3β-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-3β molecular alterations were detected in approximately 1% of solid tumors, tumors with GSK-3β mutations displayed a microenvironment with increased infiltration of B cells, and GSK-3β mutations were associated with increased PD-L1 expression in selected histologies. These results advance the understanding of GSK-3β complex signaling network interfacing with key pathways involved in carcinogenesis and immune response.
Insights
Genomic alterations in Glycogen synthase kinase-3β (GSK-3β) occur in approximately 1% of solid tumors. GSK-3β mutations are linked to altered immune cell infiltration and increased PD-L1 expression in specific cancer types.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Glycogen synthase kinase-3β (GSK-3β) is a kinase involved in cancer pathogenesis, cell-cycle regulation, apoptosis, and immune response.
- Small-molecule GSK-3β inhibitors are in clinical trials, but the genomic landscape of GSK-3β alterations in cancer is not well understood.
Purpose of the Study:
- To analyze the genomic alterations of GSK-3β across a large cohort of human malignancies.
- To investigate the relationship between GSK-3β mutations, tumor immune microenvironment, and PD-L1 expression.
Main Methods:
- Analysis of >100,000 tumors from two databases to identify GSK-3β alterations (mutations and copy-number variations).
- Assessment of GSK-3β mRNA expression and immune cell infiltration across cancer types.
- Comparison of PD-L1 expression in GSK-3β-mutated versus wild-type tumors.
Main Results:
- GSK-3β alterations were found in approximately 1% of solid tumors, with most mutations in the kinase domain and substrate binding pocket.
- Uterine endometrioid carcinoma showed the highest mutation rate (4%); copy-number variations were frequent in squamous histologies.
- GSK-3β mutations correlated with increased infiltration of B cells, monocytes, dendritic cells, neutrophils, and endothelial cells, and higher PD-L1 expression in colorectal, endometrial, melanoma, ovarian, and uterine sarcoma cancers.
Conclusions:
- GSK-3β molecular alterations are present in a small fraction of solid tumors.
- GSK-3β mutations are associated with a distinct tumor immune microenvironment characterized by increased immune cell infiltration.
- These findings highlight the complex interplay between GSK-3β signaling, cancer development, and immune response, potentially informing therapeutic strategies.
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