Does Chemo Induce Cancer Recurrence in ALL Survivors?

Chemotherapy-induced mutations may cause drug resistance in some pediatric acute lymphocytic leukemia (ALL) survivors, leading to a recurrence, according to a study published in Blood.

Researchers performed whole-genome sequencing of 103 diagnosis-relapse-germline trios and ultra-deep sequencing of 208 serial samples in 16 patients.

Treatment-associated relapse

Relapse-specific somatic alterations were enriched in 12 genes involved in drug response: NR3C1, NR3C2, TP53, NT5C2, FPGS, CREBBP, MSH2, MSH6, PMS2, WHSC1, PRPS1, and PRPS2. The prevalence of these alterations occurred in 17% in very early relapse (less than nine months from diagnosis), 65% in early relapse (nine to 36 months), and 32% in late relapse (more than 36 months) groups.

Two novel relapse-specific mutational signatures, one of which was caused by thiopurine treatment based on in vitro drug exposure experiments, were identified in early and late relapses but were absent from 2,540 pan-cancer diagnosis samples and 129 relapses not related to ALL. The novel signatures were detected in 27% of relapsed ALLs and were responsible for 46% of acquired resistance mutations in NT5C2, PRPS1, NR3C1, and TP53.

“Our study reveals the evolution dynamics of pediatric ALL, which suggest for the first time that chemotherapy treatment, particularly thiopurines, can cause mutations that lead to drug resistance in patients,” said coauthor Jinghui Zhang, PhD, chair of the St. Jude Children’s Research Hospital Department of Computational Biology, in a press release.

“This suggests drug resistance is not a foregone conclusion,” said coauthor Jun J. Yang, PhD, of the St. Jude Departments of Oncology and Pharmaceutical Sciences. “It may be preventable through changes in the dosage or timing of treatment.”

Coauthor Ching-Hon Pui, MD, chair of the St. Jude Department of Oncology, said screening relapsed patients for drug-resistance mutations may be indicated.