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

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.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm derived from the balanced reciprocal translocation of chromosomes 9 and 22 t (9q34 and 22q11), which leads to the formation of the Philadelphia chromosome and fusion of the BCR-ABL genes. The first-line treatment for CML is imatinib, a tyrosine kinase inhibitor that acts on the BCR-ABL protein. However, even though it is a target-specific drug, about 25% of patients do not respond to this treatment. The resistance mechanisms involved in this process have been investigated and studies have shown that germinal alterations can influence this mechanism. The aim of this work was to investigate 32 polymorphisms in 24 genes of carcinogenic pathway to verify the influence of these genetic variants on the response to treatment with imatinib. Our results demonstrated that individuals with the recessive GG genotype for the rs2372536 variant in the ATIC gene are approximately three times more likely to experience treatment failure with imatinib (p = 0.045, HR = 2.726, 95% CI = 0.9986–7.441), as well as individuals with the TT genotype for the rs10821936 variant in the ARID5B gene, who also have a higher risk for treatment failure with imatinib over time (p = 0.02, HR = 0.4053, IC 95% = 0.1802–0.911). In conclusion, we show that variants in the ATIC and ARIDB5 gene, never screened in previous studies, could potentially influence the therapeutic response to imatinib in patients treated for CML.

In Brazil, Acute lymphoid leukemia (ALL) is the leading cause of cancer deaths in children and adolescents. Treatment toxicity is one of the reasons for stopping chemotherapy. Amerindian genomic ancestry is an important factor for this event due to fluctuations in frequencies of genetic variants, as in the NUDT15 and SLC22A1 genes, which make up the pharmacokinetic and pharmacodynamic pathways of chemotherapy. This study aimed to investigate possible associations between NUDT15 (rs1272632214) and SLC22A1 (rs202220802) gene polymorphism and genomic ancestry as a risk of treatment toxicities in patients with childhood ALL in the Amazon region of Brazil. The studied population consisted of 51 patients with a recent diagnosis of ALL when experiencing induction therapy relative to the BFM 2009 protocol. Our results evidenced a significant association of risk of severe infectious toxicity for the variant of the SLC22A1 gene (OR: 3.18, p = 0.031). Genetic ancestry analyses demonstrated that patients who had a high contribution of African ancestry had a significant protective effect for the development of toxicity (OR: 0.174; p = 0.010), possibly due to risk effects of the Amerindian contribution. Our results indicate that mixed populations with a high degree of African ancestry have a lower risk of developing general toxicity during induction therapy for ALL. In addition, individuals with the SLC22A1 variant have a higher risk of developing severe infectious toxicity while undergoing the same therapy.

Genetic variations in PCLO have been associated with different pathologies in global literature, but there are no data regarding this gene in Native American populations. The Amazonian Native American populations have lower genetic diversity and are more different from other continental groups. We investigated 18 genetic variants in the PCLO gene in Amazonian indigenous and compared our results with the ones found in global populations, which were publicly available in the 1000 Genomes Project, gnmAD and ABraOM databases. The results demonstrated that the variants of the PCLO, especially rs17156844, rs550369696, rs61741659 and rs2877, have a significantly higher frequency in Amerindian populations in comparison with other continental populations. These data outline the singular genetic profile of the Native American population from the Brazilian Amazon region.