Structural Profiles of p53 Gene Mutations Predict Clinical Outcome in Diffuse Large B-Cell Lymphoma: An International Collaborative Study.

Mutations of the p53 tumor suppressor gene have been associated with a poor clinical outcome in some series of diffuse large B-cell lymphoma (DLBCL). However, conflicting results have been reported in other studies. The purpose of this study was to analyze the p53 mutations in DLBCL from twelve centers, and to correlate the structural profiles of the mutations with clinical outcome. The p53 mutations were identified in 102 of 477 cases of DLBCL for a frequency of 21.4%. These included 92 missense mutations, 5 nonsense mutations, 4 deletions, and 1 insertion. The presence of any p53 mutation correlated with poor overall survival (OS; P=0.002). Sixty-two of 102 cases (61%) had mutations in the DNA binding domains of the p53 gene, and the mutations in the DNA-binding domains were found to be the most important predictor of poor OS (P<0.001). In contrast, mutations in the non-DNA binding domains did not correlate with OS (P=0.158). The 5-year survival rate was 24% in patients with any p53 mutation (median survival=1.33 yr) and 19% of patients with the DNA-binding domain mutations (median survival=1.0 yr) compared to 41% for those with wild type p53 (wt-p53, median survival=4.5 yr). The complete remission rate was 57% in patients with any p53 mutation and 54% in patients with the DNA-binding domain mutations compared to 69% for those with wt-p53. Of the mutations in the DNA-binding domains, patients with mutations in the loop-sheet-helix motifs (Loop L1-S10-H2, 20% of all mutations) and DNA minor binding groove motif (Loop L3, 22% of all mutations) had significantly decreased OS (P=0.002). In contrast, OS was not significantly decreased for patients with mutations in Loop L2 (18% of all mutations). Multivariate analysis confirmed that the International Prognostic Index, age, tumor size, serum lactate dehydrogenase, and mutations in the DNA binding motifs were independent predictors of OS. The p53 mutation profile was also found to stratify germinal center B-cell-like DLBCL, but not activated B-cell-like DLBCL, into molecularly distinct subsets with different clinical outcomes. This study demonstrates the importance of the mutational profile in the DNA binding domains of the p53 gene for predicting clinical outcome and refining current prognostic models including gene expression profiling in patients with DLBCL.