Inherited TP53 variants may be crucial for acute lymphoblastic leukemia (ALL) leukemogenesis and response to treatment, according to a study published in the Journal of Clinical Oncology.1

Li-Fraumeni syndrome, which involves an inherited loss of TP53 function, carries a high cancer risk, with 50% of patients developing cancer within the first 30 years of life. Some research also suggests that germline TP53 variants may be involved in the development of pediatric ALL, particularly hypodiploid ALL, which carries a worse prognosis than other varieties.

For this study, researchers “performed a comprehensive screening of TP53 germline variation in children who were enrolled in nationwide frontline ALL trials to identify leukemia risk variants in this gene and evaluate their association with clinical features and treatment outcomes.”

Just over 3800 children were enrolled from AALL0232 (ClinicalTrials.gov Identifier: NCT00075725) and P9900 (ClinicalTrials.gov Identifier: NCT00005603), 2 frontline clinical trials sponsored by the Children’s Oncology Group. Using targeted sequencing, the researchers identified 49 rare TP53 variants in 2% of enrolled patients. Twenty-two of these variants were ALL-pathogenic.

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Compared with healthy individuals, patients with ALL were more than 5 times as likely to have a TP53 pathogenic variant (odds ratio, 5.2). Patients with TP53 pathogenic variants were much more likely and to have hypodiploid ALL than others (65.4% vs 1.2%, respectively), and had worse disease outcomes.

Patients with TP53 pathogenic variants had a 5-year cumulative risk of second cancers of 25.1%; this figure was only .7% among patients without these variants. This finding suggests, according to the authors, that patients with TP53 pathogenic variants should be pre-emptively monitored for second cancers.

The authors concluded that “our findings strongly point to germline TP53 variants—and inherited genetic variation in general—as an important determinant of ALL leukemogenesis and treatment response.”

Reference

  1. Qian M, Cao X, Devidas M, et al. TP53 germline variations influence the predisposition and prognosis of B-cell acute lymphoblastic leukemia in children. J Clin Oncol. 2018 Jan 4. doi: 10.1200/JCO.2017.75.5215 [Epub ahead of print]