Prognostic Role of SOCS1 Mutations in Diffuse Large B-Cell Lymphoma

Purpose: This study investigates the prognostic impact of SOCS1 mutations in diffuse large B-cell lymphoma (DLBCL) and explores the underlying biological mechanisms, focusing on immune regulation and cellular metabolism. Materials and Methods: We included 2,590 DLBCL patients from 7 publicly databases (integrated cohort) and 202 additional DLBCL cases from our institution (JSPH cohort). Next-generation sequencing (NGS) was used to detect SOCS1 mutations in DLBCL patients. We analyzed the association between these mutations and overall survival (OS) and progression-free survival (PFS). Additionally, we examined how SOCS1 mutations might influence immune responses, cellular metabolism, and signaling pathways, particularly in the ST2 subtypes of DLBCL. Results: In the integrated cohort, 15.1% of patients carried SOCS1 mutations, with 12.3% of these mutations located in the SOCS-BOX domain. SOCS1 mutations were found to be more frequent in the GCB and ST2 subtypes of DLBCL. In the integrated cohort, patients with SOCS1 mutations had significantly better OS (p=0.015) and PFS (p=0.007). Mutations located in the SOCS-BOX domain were associated with even better OS (p=0.015) and PFS (p=0.012). In the JSPH cohort, transcriptomic analyses indicated enhanced interferon signaling, immune activation, and downregulation of metabolic pathways in SOCS1-mut cases, especially within the ST2 subtype. These alterations may contribute to a more favorable tumor microenvironment and improved clinical outcomes. Conclusion: SOCS1 mutations, particularly those in the SOCS-BOX domain, are associated with improved prognosis in DLBCL. By promoting immune activation and inhibiting cellular metabolism, these mutations may not only serve as prognostic biomarkers but also provide insights into potential therapeutic avenues.