Mutational Spectrum of T-Cell Large Granular Lymphocytic Leukemia: Insights From the AACR Project GENIE Consortium

Abstract Background/Aim: T-cell large granular lymphocyte leukemia (T-LGLL) is a rare, indolent lymphoproliferative disorder of cytotoxic T cells in the peripheral blood, bone marrow, and spleen. This analysis was conducted to characterize genomic alterations and highlight potential therapeutic targets, with the goal of refining the molecular landscape of T-LGLL by emphasizing population-specific biomarkers. Materials and Methods: This study utilized the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database to identify common gene mutations. Using the AACR GENIE database, a retrospective analysis of T-cell large granular lymphocyte leukemia (T-LGLL) samples was performed. The data was evaluated by extracting patient demographics and excluding synonymous mutations from consideration. Statistical significance was assessed using chi-squared tests and computational analyses in RStudio (R Foundation for Statistical Computing, Boston, MA, USA). Somatic mutations and chromosomal copy number variations were evaluated, with statistical significance defined as p=0.001. Results: Frequently observed somatic mutations included STAT3 (41.7%), STAT2 (20.9%), KMT2D (11.3%), SETD1B (8.7%), TP53 (7.0%), TNFAIP3 (6.1%), DNMT3A (5.2%), FAS (4.3%), SMARCA4 (3.5%), EPHB1 (2.6%), KSR2 (2.6%), ALOX12B (2.6%), EGFR (2.6%), DDX3X (7.0%), and IKZF3 (1.7%). When stratified by demographic variables, males and White patients demonstrated a higher frequency of mutations. Conclusion: This study provides a comprehensive genomic profile of T-LGLL, identifying recurrent somatic mutations and commonly affected pathways. Notably, frequent alterations were observed in the FAS-FASL signaling pathway, underscoring its potential as a target for therapeutic development.