Characterization of pharmacogenetic markers related to Acute Lymphoblastic Leukemia toxicity in Amazonian native Americans population

Abstract

Acute Lymphoblastic Leukemia (ALL) is the most common cancer in children. Differences are found among ethnic groups in the results of the treatment of pediatric ALL. in general, children with a high level of native American ancestry tend to respond less positively to ALL treatments, which may be related to specific genomic variants found in native American groups. Despite the evidence, few data are available on the distribution of the pharmacogenomic variants relevant to the treatment of ALL in traditional Amerindian populations, such the those of the Amazon region. Given this, the present study investigated 27 molecular markers related to the treatment of ALL in Amerindians from Brazilian Amazonia and compared the frequencies with those recorded previously on five continents, that are available in the 1,000 Genomes database. The variation in the genotype frequencies among populations was evaluated using fisher's exact test. the false Discovery Rate method was used to correct the results of the multiple analyses. Significant differences were found in the frequencies of the majority of markers between the Amerindian populations and those of other regions around the world. These findings highlight the unique genetic profile of the indigenous population of Brazilian Amazonia, which may reflect a distinct therapeutic profile for the treatment of ALL in these populations. Acute Lymphoblastic Leukemia (ALL) is the most common cancer subtype found in children, accounting for almost 80% of cases 1,2. The treatment of ALL is based on the application of a combination of chemotherapeutic agents. Two drugs, 6-mercaptopurine (6-MP) and Methotrexate (MTX), are the principal types of medication used during the consolidation and maintenance phases of the treatment of ALL. Survival rates are relatively high, at approximately 80%, although around 20% of the children treated present serious toxicological complications that frequently lead to the interruption of the treatment. The variation in the toxicological response of patients to the treatment of ALL may be determined by different polymorphic variants of the genes involved in the pharmacokinetics and/or pharmacodynamics of these drugs 3,4. Ethnic differences have been recognized

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

“…Our research group recently identified a high frequency of the CC genotype of the TPMT*3C variant in traditional indigenous populations of the Amazon region. This frequency was significantly different from those recorded in other populations worldwide [ 17 ], which clearly indicates that this polymorphism is more frequent in Amer-Indian populations and in populations admixed with these groups, as the population investigated in the present study. These findings reinforce the conclusion that pharmacogenetic data obtained from homogeneous ethnic groups cannot be applied to highly admixed populations.…”

“…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 ]. In fact, 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 ].…”

Correlation of Genetic Variants and the Incidence, Prevalence and Mortality Rates of Acute Lymphoblastic Leukemia

“…A large fluctuation in ALL’s epidemiological rates is observed worldwide [ 1 ]. One of the risk factors that may contribute to this variability is the inherent genetic factors of each ethnicity [ 7 , 10 , 11 ]. Several genomic studies with a large number of patients show that genetic variants may act as risk factors for ALL in populations with different patterns of ethnic composition [ 13 , 14 ].…”

“…This disparity observed between populations occurs due to the presence of genetic polymorphisms and intrinsic environmental factors to which these groups are exposed [ 10 ]. Some studies have already highlighted Amerindian ancestry and mixed populations as risk factors for developing of toxicity in ALL [ 9 , 11 , 12 , 13 ]. Therefore, our study aimed to investigate the correlation between genetic polymorphisms involved in biological pathways for ALL and their impacts on incidence, mortality, and prevalence rates in different world populations.…”

Impact of Variants in the ATIC and ARID5B Genes on Therapeutic Failure with Imatinib in Patients with Chronic Myeloid Leukemia

“…Another factor that can interfere with treatment responses is the genetic composition of a population. It is known that the responses among populations vary worldwide, due to different frequencies of genetic variants in genes involved in absorption, distribution, metabolism, and excretion (ADME) of drugs [ 11 , 12 , 13 ]. In addition, in this study, the population investigated is highly mixed, and it is important to carry out a genomic control based on genetic ancestry, therefore, that there is no population substructuring and ancestry is not a confounding factor in the analyses [ 14 , 15 ].…”