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.

Analysis of Very Important Pharmacogenomics Variants in the Chinese Lahu Population

“…A high-frequency CC genotype of the TPMT*3C variant was found in traditional indigenous people in the Amazon region. 23 Compared with the other 11 populations, TPMT rs1142345 variants in the Lahu population are statistically different. The C allele is associated with mercaptopurine exposure in children with leukemia when compared with the T allele.…”

“…The relationship between the polymorphism of rs1142345 and the risk of acute lymphoblastic leukemia has been widely reported. 23 , 24 The personalized medication (mercaptopurine) for acute lymphoblastic leukemia of the Lahu ethnic group is worthy of attention.…”

“…The relationship between the polymorphism of rs1142345 and the risk of acute lymphoblastic leukemia has been widely reported. 23,24 The personalized medication (mercaptopurine) for acute lymphoblastic leukemia of the Lahu ethnic group is worthy of attention. Furthermore, we found that VKORC1 rs9934438 (A>G) was significantly different in Lahu compared to the other 11 populations as well.…”

Precursor B‐cell acute lymphoblastic leukaemia—a global view

“…Epidemiological studies have demonstrated that ALL has a higher incidence rate in the Latino population with outcomes in both paediatric cases and adults drastically worse than international standards. The underlying cause of these observations is unknown, although several hypotheses have been postulated including disparities in socioeconomic status, environmental risks, inherited genetic mutations, or a combination of factors 1,2 …”

Pharmacogenomic Determinants of Interindividual Drug Response Variability: From Discovery to Implementation

“…In addition to the GWAS by Cismaru et al [ 1 ], several candidate gene pharmacogenomic studies were also reported in this Special Issue. For example, de Carvalho et al [ 2 ] employed a targeted genotyping panel of candidate genes and variants to study children from Brazil with acute lymphoblastic leukemia (ALL) undergoing chemotherapy with 6-mercaptopurine (6-MP) and methotrexate (MTX). An association was identified between the risk of death and the TPMT rs1142345 variant allele, which is found on both the TPMT*3A and *3C haplotypes.…”