Heterogeneous TP53 mutation subtypes define prognostic classification in Mantle Cell Lymphoma

Abstract Background: Mantle cell lymphoma (MCL) is a biologically aggressive B-cell malignancy with marked clinical variability. Among its molecular drivers, mutations in the TP53 gene have emerged as pivotal determinants of disease behavior and therapeutic resistance. However, the prognostic implications of distinct TP53 mutation subtypes remain insufficiently defined. In this study, we systematically evaluated how variation in TP53 mutation type and structural location correlates with clinical presentation and survival outcomes in patients with MCL. Methods: We retrospectively analyzed 215 patients diagnosed with mantle cell lymphoma at Peking University Third Hospital between August 2017 and January 2024. For each case, targeted sequencing of the TP53 gene was performed, alongside systematic collection of clinical characteristics and survival data. Statistical evaluation included both descriptive summaries and multivariable Cox proportional hazards modeling. Results: TP53-mutated cases were significantly associated with aggressive disease features, including elevated Ki67 proliferation index (p = 0.008), higher composite MIPI-c scores (p = 0.032), and increased prevalence of blastoid or pleomorphic morphologic variants (p = 0.028). Among the mutations detected, missense variants predominated (75.6%), with G:C to A:T transitions being the most frequent substitution (48.31%). Notably, 92.41% of mutations localized to the DNA-binding domain (DBD), with the majority clustering in exons 5 through 8 (82.05%). The prognostic significance of TP53 mutations varied substantially depending on their structural localization. When mapped onto the gene architecture (Figure 1), a distinct risk stratification emerged. Mutations at the canonical hotspot residues G245 and R273 were associated with the poorest survival outcomes (OS: HR = 3.67; PFS: HR = 2.83). Alterations within zinc-binding motifs (OS: HR = 3.00; PFS: HR = 1.34) and the broader DNA-binding domain (DBD) (OS: HR = 2.86; PFS: HR = 1.85) conferred intermediate risk. In contrast, mutations located outside the DBD (OS: HR = 0.88; PFS: HR = 0.66) and TP53 wild-type cases (OS: HR = 0.30; PFS: HR = 0.51) were associated with more favorable prognoses. Based on these patterns, we established a three-tier classification of TP53 alterations for further analysis. This grouping revealed statistically significant differences in both overall survival (p = 0.015) and progression-free survival (p = 0.026). To explore the biological underpinnings of this prognostic gradient, we performed functional annotation using publicly available datasets (http://www.rescuep53.net/), focusing on transactivation and the capacity to inhibit cell growth. G245 and R273 mutations showed profoundly diminished transactivation ability and minimal inhibitory effects on proliferation, suggesting near-complete loss of TP53 tumor suppressor function. Conclusion In summary, TP53 mutations in MCL follow a consistent biological and prognostic stratification. The combination of gene location, functional disruption, and survival data supports a model in which G245/R273 mutations define a high-risk group, while non-DBD alterations are relatively indolent. This framework provides a mechanistic rationale for incorporating TP53 mutation profiling into future MCL risk models.