Comprehensive analysis of TP53 mutation characteristics and identification of patients with inferior prognosis and enhanced immune escape in diffuse large B-cell lymphoma

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous lymphatic malignancy. The role of TP53 gene alterations in DLBCL remains unclear. Methods: We performed a comprehensive analysis of the genomic characteristics of TP53 through targeted next-generation sequencing (n=176), RNA-sequencing (n=152), and circulating tumor DNA sequencing (n=38). Results: TP53 was frequently mutated in DLBCL; most TP53 mutations occurred in the DNA-binding domain (DBD). However, TP53 alone is insufficient to effectively differentiate the risk of DLBCL, even when only considering mutations in the DBD region. However, CD58 mutations, which are mutually exclusive from TP53 mutations, in combination with TP53 mutations, could significantly differentiate the prognosis of DLBCL. The survival of patients with either one of the mutually exclusive mutation patterns, namely, TP53MUT&CD58WT or TP53WT&CD58MUT, was inferior to those harboring both wild-type TP53 and CD58. Notably, patients with the TP53WT&CD58MUT mutation pattern had the worst outcome and were characterized by an enhanced immune escape, including features such as the abundant infiltration of inflammatory cells and upregulation of inhibitory immunomodulatory molecules; these patients represent the candidate populations for immune therapy. Conclusions: Our findings indicated that the mutation patterns of TP53 and CD58 accurately stratified patients with DLBCL to permit the optional immunotherapy.