FPGS relapse-specific mutations in relapsed childhood acute lymphoblastic leukemia
Journal
Scientific Reports
Journal Volume
10
Journal Issue
1
Pages
12074
Date Issued
2020
Author(s)
Zhang, Hui
Ho, Bing-Ching
Yu, Chih-Hsiang
Chang, Chia-Ching
Hsu, Yin-Chen
Ni, Yu-Ling
Lin, Kai-Hsin
Chen, Shu-Huey
Wu, Kang-Hsi
Wang, Shih-Chung
Pui, Ching-Hon
Yang, Jun J
Zhang, Jinghui
Lin, Dong-Tsamn
Ma, Xiaotu
Abstract
Although the cure rate for childhood acute lymphoblastic leukemia (ALL) has exceeded 80% with contemporary therapy, relapsed ALL remains a leading cause of cancer-related death in children. Relapse-specific mutations can be identified by comprehensive genome sequencing and might have clinical significance. Applying whole-exome sequencing to eight triplicate samples, we identified in one patient relapse-specific mutations in the folylpolyglutamate synthetase (FPGS) gene, whose product catalyzes the addition of multiple glutamate residues (polyglutamation) to methotrexate upon their entry into the cells. To determine the prevalence of mutations of the FPGS mutations, and those of two important genes in the thiopurine pathway, NT5C2 and PRPS1, we studied 299 diagnostic and 73 relapsed samples in 372 patients. Three more FPGS mutants were identified in two patients, NT5C2 mutations in six patients, and PRPS1 mutants in two patients. One patient had both NT5C2 and PRPS1 mutants. None of these alterations were detected at diagnosis with a sequencing depth of 1000X, suggesting that treatment pressure led to increased prevalence of mutations during therapy. Functional characterization of the FPGS mutants showed that they directly resulted in decreased enzymatic activity, leading to significant reduction in methotrexate polyglutamation, and therefore likely contributed to drug resistance and relapse in these cases. Thus, besides genomic alterations in thiopurine metabolizing enzymes, the relapse-specific mutations of FPGS represent another critical mechanism of acquired antimetabolite drug resistance in relapsed childhood ALL. ? 2020, The Author(s).
SDGs
Other Subjects
peptide synthase; tetrahydrofolate synthase; tumor marker; acute lymphoblastic leukemia; adolescent; allele; child; drug resistance; female; genetic association study; genetic predisposition; genetics; genotype; high throughput sequencing; human; infant; male; mutation; preschool child; prognosis; Adolescent; Alleles; Biomarkers, Tumor; Child; Child, Preschool; Drug Resistance, Neoplasm; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; High-Throughput Nucleotide Sequencing; Humans; Infant; Male; Mutation; Peptide Synthases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis
Publisher
Nature Research
Type
journal article