Association between the TPMT*3C (rs1142345) Polymorphism and the Risk of Death in the Treatment of Acute Lymphoblastic Leukemia in Children from the Brazilian Amazon Region

Abstract

Acute lymphoblastic leukemia (ALL) is the leading cause of death from pediatric cancer worldwide. However, marked ethnic disparities are found in the treatment of childhood ALL with less effective results and higher mortality rates being obtained in populations with a high level of Native American ancestry. Genetic variations of the patient can affect resistance to ALL chemotherapy and potentially play an important role in this disparity. In the present study, we investigated the association of 16 genetic polymorphisms with the cell and metabolic pathways of the chemotherapeutic agents used in the treatment of ALL with the risk of death in treating childhood ALL in patients with a high contribution of Amerindian ancestry, coming from the Brazilian Amazon. The study included 121 patients with B-cell ALL treated with the BFM-2002 protocol. We are the first to identify the association between the TPMT gene rs1142345 polymorphism and the high risk of death in treating childhood ALL. Patients with the CC genotype had an approximately 25.5 times higher risk of dying during treatment of the disease than patients with other genotypes (p = 0.019). These results may help elucidate how the patient's genetic characteristics contribute to the mortality disparity in populations with a high contribution of Native American ancestry. The rs1142345 variant of the TPMT gene could be used as a potential marker to early stratify patients at high risk of death in treating childhood ALL in the investigated population.

Keywords: Amazon; TPMT; acute lymphoblastic leukemia; admixed populations; ancestry; mortality; pediatrics; pharmacogenetics; polymorphism.

Figure 1

Representation of individuals’ inter-ethnic admixtures. Patients with ALL are represented by a dot in purple and their location on the graph corresponds to the mixture ratios. The mixture is estimated by comparison with parent populations of individuals represented in the triangle vertices: European (EUR), Amerindian (AMER), and African (AFRIC).

Figure 2

Distribution of TPMT_rs1142345 variants according to the 6-MP dose used in the maintenance phase of the ALL treatment (a) between carriers and non-carriers of the C allele (b) and among patients with genotype CC vc CT + CC (c).