Haiyan Zhang, Xiang Zhang, Jinghan Wang, Xuewu Zhang, Yunfei Lv, Yanan Zhu, Ye X, Juying Wei, Min Yang, Gaixiang Xu, Chunmei Yang, Haitao Meng, Wanzhuo Xie, Jie Jin, Hongyan Tong, Wenjuan Yu
Whether TP53 mutation can serve as a simplified prognostic surrogate for complex genomic classifiers in diffuse large B-cell lymphoma (DLBCL) remains unclear. we comprehensively analyzed a retrospective cohort of 444 newly diagnosed DLBCL patients. TP53 mutation was an independent prognostic factor for inferior overall survival (OS) and progression-free survival (PFS) (both P < 0.001), correlating with inferior response to R-CHOP and enrichment in refractory/relapsed disease. Furthermore, multivariate analysis revealed that the adverse prognostic effect of TP53 mutation was predominantly driven by its impact within the germinal center B-cell-like (GCB) subtype, as evidenced by a significant statistical interaction. Notably, the combination of TP53 mutation and double-expression lymphoma (DEL) identified an ultra-high-risk group with synergistic poor survival. The prognostic impact was not modified by the specific protein domain, mutation burden, or gain- versus loss-of-function nature of the mutations. However, a high variant allele frequency (VAF) ≥ 53% identified a subgroup with worse survival. Finally, we adapted a p53 immunohistochemical classification from ovarian/endometrial cancer to enhance TP53 mutation prediction: overexpression (> 80%) or complete absence (< 1%) as high-risk, and heterogeneity (1%-80%) as low-risk. This approach achieved 72.5% sensitivity and 97.4% specificity, with specificity surpassed conventional ≥ 50% cutoff (P < 0.001). In conclusion, TP53 mutation is a critical, context-dependent biomarker in DLBCL, and its combination with DEL identifies a clinically actionable, ultra-high-risk group. The p53 IHC classifier shows promise as a rapid screening tool, warranting further validation.