TP53 mutation heterogeneity reveals distinct prognoses in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an uncommon and aggressive type of B-cell non-Hodgkin lymphoma, wherein TP53 mutations play a critical role. This study analyzed the effect of different TP53 mutations on the clinical characteristics and prognosis of patients with MCL. TP53 sequencing data and clinical and prognostic information were collected from 215 patients with MCL treated at Peking University Third Hospital between August 2017 and December 2022. Furthermore, descriptive and Cox regression analyses were also performed. Our findings revealed the association between TP53 mutations and higher Ki67 levels (p = 0.008), elevated combined MCL International Prognostic Index (MIPI-c; p = 0.032), blastoid/pleomorphic subtypes (p = 0.020) and ≥ 2 treatment lines (p = 0.026). Missense mutations (75.6%; G: C > A:T [48.31%]) were the predominant mutation type, occurring within the DNA-binding domain (DBD; 92.41%) and concentrated in exons 5–8 (82.05%). TP53 mutations significantly affected overall survival (OS; p = 0.0091) and progression-free survival (PFS; p = 0.029), and the extent of the impact on prognosis was dependent on the location of the mutations. Following MIPI-c adjustment, multivariate analysis revealed the detrimental effects of DBD (OS: hazard ratio [HR] = 3.06) and R273/G245 (OS: HR = 7.95) mutations (p = 0.012). G245 and R273 mutations lead to significantly reduced transactivation levels and impaired cell proliferation inhibition (p < 0.001), providing mechanistic evidence that supports their association with poorer prognosis in MCL patients.