The Role of SLC22A1 and Genomic Ancestry on Toxicity during Treatment in Children with Acute Lymphoblastic Leukemia of the Amazon Region

Abstract

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.

Effect of American genomic ancestry on severe toxicities in children with acute lymphoblastic leukemia in the Amazon region

“…Ethnic differences in survival rates after childhood ALL vary worldwide [9][10][11][12][13][14], with Hispanic-origin children exhibiting poorer survival rates. Interestingly, Hispanic patients treated in high-income countries showed lower survival rates, highlighting ancestral genomic bias as a contributing factor to these outcomes.…”

The Future of Pharmacogenomics Requires New Discoveries and Innovative Education

“…Despite known ethnical differences in genotype frequencies across populations, some interesting associations have been reported. In this Special Issue, Fernandes et al described how genetic ancestry can significantly alter the response to drugs [ 4 ]. Studying children in the Amazon region of Brazil, authors investigated possible associations between NUDT15 (rs1272632214) and SLC22A1 (rs202220802) gene polymorphisms and response to treatment (BFM 2009 protocol) in acute lymphoid leukemia patients.…”

“…Three reviews focused on pharmacogenomics in oncology, psoriasis, and monogenic diabetes [ 6 , 7 , 8 ]. Furthermore, three research studies elucidate molecular aspects [ 9 ], genetic associations in large populations [ 5 ], and in selected ancestries [ 4 ].…”