TP53
mutation (
TP53
-mut) correlates with inferior survival in many cancers, whereas its prognostic role in diffuse large B-cell lymphoma (DLBCL) is still in controversy. Therefore, more precise risk stratification needs to be further explored for
TP53
-mut DLBCL patients. A set of 2637 DLBCL cases from multiple cohorts, was enrolled in our analysis. Among the 2637 DLBCL patients, 14.0% patients (370/2637) had
TP53
-mut. Since missense mutations account for the vast majority of
TP53
-mut DLBCL patients, and most non-missense mutations affect the function of the P53 protein, leading to worse survival rates, we distinguished patients with missense mutations. A
TP53
missense mutation risk model was constructed based on a 150-combination machine learning computational framework, demonstrating excellent performance in predicting prognosis. Further analysis revealed that patients with high-risk missense mutations are significantly associated with early progression and exhibit dysregulation of multiple immune and metabolic pathways at the transcriptional level. Additionally, the high-risk group showed an absolutely suppressed immune microenvironment. To stratify the entire cohort of
TP53
-mut DLBCL, we combined clinical characteristics and ultimately constructed the
TP53
Prognostic Index (TP53PI) model. In summary, we identified the truly high-risk
TP53-
mut DLBCL patients and explained this difference at the mutation and transcriptional levels.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12964-024-01765-w.