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.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and the principal cause of death from malignant diseases in childhood [1,2,3]
A number of studies have concluded that the differential mortality rates in Hispanics with ALL are related to a genetic predisposition linked to the Native American ancestry of these populations [10,11,12,13,14]
The present study investigated the possible relationship between 16 genetic markers involved in the 6-MP and MTX pharmacological pathways, and the risk of death in pediatric patients with ALL in the Brazilian Amazon
Summary
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and the principal cause of death from malignant diseases in childhood [1,2,3]. The chemotherapeutic drugs 6-mercaptopurine (6-MP) and methotrexate (MTX) are the principal compounds used for treating ALL, which helps increase survival rates by around 90% [4]. This treatment fails in 20% of pediatric patients, which results in high mortality rates [5,6,7]. Hispanic children with ALL treated using the same therapeutic regimens as those of European descent have higher mortality rates [8,9]. This indicates a differential role of genetic factors. Many of the genetic variants associated with the toxicity and relapses in the treatment of ALL have been found more frequently in Native American populations or in populations with a high degree of miscegenation involving this ethnic group [15,16,17,18]
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