Ancestry and TPMT-VNTR Polymorphism: Relationship with Hematological Toxicity in Uruguayan Patients with Acute Lymphoblastic Leukemia.
Front Pharmacol
; 11: 594262, 2020.
Article
en En
| MEDLINE
| ID: mdl-33424606
ABSTRACT
6-Mercaptopurine (6-MP) is a thiopurine drug widely used in childhood acute lymphoblastic leukemia (ALL) therapy. Genes such as TPMT and NUDT15 have an outstanding role in 6-MP metabolism. Mutations in both genes explain a significant portion of hematological toxicities suffered by ALL Uruguayan pediatric patients. A variable number tandem repeat in the TPMT promoter (TPMT-VNTR) has been associated with TPMT expression. This VNTR has a conservative architecture (AnBmC). To explore new causes of hematological toxicities related to ALL therapy, we genotyped the TPMT-VNTR of 130 Uruguayan pediatric patients. Additionally, individual genetic ancestry was estimated by 45 ancestry-informative markers (AIMs). Hematological toxicity was measured as the number of leukopenia events and 6-MP dose along the maintenance phase. As previously reported, we found TPMT*2 and TPMT*3C alleles were associated to TPMT-VNTR A2BC and AB2C, respectively. However, contrasting with other reports, TPMT*3A allele was found in a heterogeneous genetic background in linkage equilibrium. Patients carrying more than 5 A repeats present a significant higher number of leukopenia events among patients without TPMT and/or NUDT15 variants. Native American ancestry and the number of A repeats were significantly correlated with the number of leukopenia events. However, the correlation between Native American ancestry and the number of leukopenia events was lost when the number of A repeats was considered as covariate. This suggests that TPMT-VNTR alleles are more relevant than Native American ancestry in the hematological toxicity. Our results emphasize that TPMT-VNTR may be used as a pharmacogenetic biomarker to predict 6-MP-related hematological toxicity in ALL childhood therapy.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Tipo de estudio:
Prognostic_studies
País/Región como asunto:
America do sul
/
Uruguay
Idioma:
En
Revista:
Front Pharmacol
Año:
2020
Tipo del documento:
Article
País de afiliación:
Uruguay
Pais de publicación:
CH
/
SUIZA
/
SUÍÇA
/
SWITZERLAND