Effect of TP53 Germline Variations on Outcomes in Pediatric B-Cell ALL

Key Points

  • TP53 pathogenic variants were more common in patients with ALL vs non-ALL controls.
  • Presence of germline pathogenic variants was associated with poorer event-free survival and overall survival.

In a study reported in the Journal of Clinical Oncology, Qian et al found that loss-of-function germline TP53 variants increase the risk of childhood B-cell acute lymphoblastic leukemia (ALL), as well as the risk of poorer response to therapy and second malignancies.

Study Details

In the study, targeted sequencing of TP53 coding regions was performed in 3,801 children from Children’s Oncology Group front-line ALL clinical trials (AALL0232 and P9900). TP53 variants were analyzed for an association with ALL presentation and treatment outcomes.

TP53 Pathogenic Variants and Outcomes

A total of 49 unique nonsilent rare TP53 coding variants were found in 77 (2.0%) of the 3,801 patients; of these, 22 variants were classified as pathogenic (loss or alteration of the DNA-binding function). TP53 pathogenic variants were more common in patients with ALL vs non-ALL controls (odds ratio = 5.2, P < .001).

Patients with pathogenic variants were older at ALL diagnosis (median = 15.5 vs 7.3 years, P < .001) and more likely to have hypodiploid ALL (65.4% vs 1.2%, P < .001). The presence of germline pathogenic variants was associated with poorer event-free survival (hazard ratio = 4.2, P < .001) and overall survival (HR = 3.9, P < .001).  Patients with pathogenic variants had a higher risk of second cancers vs those without pathogenic variants (5-year cumulative incidence = 25.1% vs 0.7%, P < .001).

The investigators concluded, “Loss-of-function germline TP53 variants predispose children to ALL and to adverse treatment outcomes with ALL therapy, particularly the risk of second malignant neoplasms.”

The study was supported by National Institutes of Health grants and the American Lebanese Syrian Associated Charities.

Jun J. Yang, PhD, of the Hematologic Malignancies Program, St Jude Children’s Research Hospital, is the corresponding author for the Journal of Clinical Oncology article. 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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