Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study

Abstract

The purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53 mutations was significantly worse than those with wild-type TP53 (P < .001). However, subsets of TP53 mutations were found to have different effects on OS. Mutations in the TP53 DNA-binding domains were the strongest predictors of poor OS (P < .001). Mutations in the Loop-Sheet-Helix and Loop-L3 were associated with significantly decreased OS (P = .002), but OS was not significantly affected by mutations in Loop-L2. A subset of missense mutations (His158, His175, Ser245, Gln248, His273, Arg280, and Arg282) in the DNA-binding domains had the worst prognosis. Multivariate analysis confirmed that the International Prognostic Index and mutations in the DNA-binding domains were independent predictors of OS. TP53 mutations also stratified patients with germinal center B cell-like DLBCL, but not nongerminal center B cell-like DLBCL, into molecularly distinct subsets with different survivals. This study shows the prognostic importance of mutations in the TP53 DNA-binding domains in patients with DLBCL.

Figures

Figure 1

Schematic representation of the TP53 gene and its mutations in diffuse large B-cell lymphoma. (A) The distribution of TP53 mutations in exons 4 to 9, (B) their relation to p53 protein structure, (C) the mutations in conserved regions, and (D) the distribution and frequency of TP53 mutations with peaks at known hot spot exons depicted.

Figure 2

Kaplan-Meier survival analysis of patients with diffuse large B-cell lymphoma stratified by TP53 mutation status. (A) Distribution pattern of TP53 mutations in the central core domain model designed from published crystal structure (red indicates patients with poor survival; green, patients with survival similar to WT group; blue, survival data unavailable). (B) Overall survival of patients with TP53 mutations versus those with WT-TP53. (C) Overall survival of patients with DNA-binding domain mutations versus those with WT-TP53. (D) Overall survival of patients with non–DNA-binding domain mutations versus those with WT-TP53.

Figure 3

Prognostic significance of TP53 mutations in specific DNA-binding motifs. (A) Overall survival of patients with mutations in the Loop-L2 domain. (B) Overall survival of patients with mutations in the Loop-L3 motif. (C) Overall survival of patients with mutations in the LSH domain.

Figure 4

Kaplan-Meier survival analysis by TP53 mutations in the molecular subtypes of diffuse large B-cell lymphoma. (A) Overall survival of patients with GCB-DLBCL with TP53 mutations. (B) Overall survival of patients with non–GCB-DLBCL with TP53 mutations. (C) Overall survival of patients with GCB-DLBCL with DNA-binding domain mutations. (D) Overall survival of patients with non–GCB-DLBCL with DNA-binding domain mutations.

Figure 5

Kaplan-Meier survival analysis of patients with diffuse large B-cell lymphoma defined by functional or structural subsets of TP53 mutations. (A) Overall survival of patients with missense TP53 mutations. (B) Overall survival of patients with TP53 mutations in direct DNA-contact codons. (C) Overall survival of patients with inactivating TP53 mutations defined by yeast functional assays. (D) Overall survival of patients with TP53 mutations in the conserved regions IV and V.