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

Overview

Journal Genes (Basel)

Publisher MDPI

Date 2022 Apr 23

PMID 35456416

Authors

Sweny de S M Fernandes

Luciana P C Leitao

Amanda de N Cohen-Paes

Laura P A Gellen

Lucas F Pastana

Darlen C de Carvalho

Antonio A C Modesto

Ana C A da Costa

Alayde V Wanderley

Carlos H V de Lima

Esdras E B Pereira

Marianne R Fernandes

Rommel M R Burbano

Paulo P de Assumpcao

Sidney E B Dos Santos

Ney P C Dos Santos

Affiliations

Soon will be listed here.

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 and genes, which make up the pharmacokinetic and pharmacodynamic pathways of chemotherapy. This study aimed to investigate possible associations between (rs1272632214) and (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 gene (OR: 3.18, = 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; = 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 variant have a higher risk of developing severe infectious toxicity while undergoing the same therapy.

Citing Articles

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

Wanderley A, de Moraes F, da Costa Nunes G, Pereira E, Leitao L, de Oliveira M Discov Oncol. 2024; 15(1):171.

PMID: 38761320 PMC: 11102409. DOI: 10.1007/s12672-024-01014-z.

Influence of Genetic Variations in miRNA and Genes Encoding Proteins in the miRNA Synthesis Complex on Toxicity of the Treatment of Pediatric B-Cell ALL in the Brazilian Amazon.

Menezes E, de Moraes F, Cohen-Paes A, Wanderley A, Pereira E, Pastana L Int J Mol Sci. 2023; 24(5).

PMID: 36901860 PMC: 10003057. DOI: 10.3390/ijms24054431.

The Future of Pharmacogenomics Requires New Discoveries and Innovative Education.

Giardina E, Zampatti S Genes (Basel). 2022; 13(9).

PMID: 36140743 PMC: 9498360. DOI: 10.3390/genes13091575.

References

Yang J, Cheng C, Devidas M, Cao X, Fan Y, Campana D . Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia. Nat Genet. 2011; 43(3):237-41. PMC: 3104508. DOI: 10.1038/ng.763. View

Arimany-Nardi C, Koepsell H, Pastor-Anglada M . Role of SLC22A1 polymorphic variants in drug disposition, therapeutic responses, and drug-drug interactions. Pharmacogenomics J. 2015; 15(6):473-87. DOI: 10.1038/tpj.2015.78. View

Lange B, Bostrom B, Cherlow J, Sensel M, La M, Rackoff W . Double-delayed intensification improves event-free survival for children with intermediate-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood. 2002; 99(3):825-33. DOI: 10.1182/blood.v99.3.825. View

Carvalho D, Wanderley A, Dos Santos A, Moreira F, de Sa R, Fernandes M . Characterization of pharmacogenetic markers related to Acute Lymphoblastic Leukemia toxicity in Amazonian native Americans population. Sci Rep. 2020; 10(1):10292. PMC: 7314857. DOI: 10.1038/s41598-020-67312-y. View

Buaboonnam J, Sripatanatadasakul P, Treesucon A, Glomglao W, Siraprapapat P, Narkbunnam N . Effect of NUDT15 on incidence of neutropenia in children with acute lymphoblastic leukemia. Pediatr Int. 2019; 61(8):754-758. DOI: 10.1111/ped.13905. View

Suarez-Kurtz G, Brisson G, Hutz M, Petzl-Erler M, Salzano F . NUDT15 Polymorphism in Native American Populations of Brazil. Clin Pharmacol Ther. 2019; 105(6):1321-1322. DOI: 10.1002/cpt.1379. View

Moradveisi B, Muwakkit S, Zamani F, Ghaderi E, Mohammadi E, Zgheib N . , , and Genetic Polymorphisms Predict 6-Mercaptopurine Toxicity in Middle Eastern Children With Acute Lymphoblastic Leukemia. Front Pharmacol. 2019; 10:916. PMC: 6718715. DOI: 10.3389/fphar.2019.00916. View

Yao S, Zhu Q, Cole P, Stevenson K, Harris M, Schultz E . Genetic ancestry and skeletal toxicities among childhood acute lymphoblastic leukemia patients in the DFCI 05-001 cohort. Blood Adv. 2021; 5(2):451-458. PMC: 7839368. DOI: 10.1182/bloodadvances.2020003060. View

Rodrigues J, Piedade de Souza T, Pastana L, Dos Santos A, Fernandes M, Pinto P . Identification of NUDT15 gene variants in Amazonian Amerindians and admixed individuals from northern Brazil. PLoS One. 2020; 15(4):e0231651. PMC: 7159207. DOI: 10.1371/journal.pone.0231651. View

10.

Shu Y, Leabman M, Feng B, Mangravite L, Huang C, Stryke D . Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc Natl Acad Sci U S A. 2003; 100(10):5902-7. PMC: 156299. DOI: 10.1073/pnas.0730858100. View

11.

Li J, Lou H, Yang X, Lu D, Li S, Jin L . Genetic architectures of ADME genes in five Eurasian admixed populations and implications for drug safety and efficacy. J Med Genet. 2014; 51(9):614-22. DOI: 10.1136/jmedgenet-2014-102530. View

12.

Ribeiro de Andrade Ramos B, DElia M, Amador M, Santos N, Emanuel Batista Santos S, Castelli E . Neither self-reported ethnicity nor declared family origin are reliable indicators of genomic ancestry. Genetica. 2016; 144(3):259-65. DOI: 10.1007/s10709-016-9894-1. View

13.

Carvalho D, Wanderley A, Amador M, Fernandes M, Cavalcante G, Pantoja K . Amerindian genetic ancestry and INDEL polymorphisms associated with susceptibility of childhood B-cell Leukemia in an admixed population from the Brazilian Amazon. Leuk Res. 2015; . DOI: 10.1016/j.leukres.2015.08.008. View

14.

Hareedy M, El Desoky E, Woillard J, Thabet R, Ali A, Marquet P . Genetic variants in 6-mercaptopurine pathway as potential factors of hematological toxicity in acute lymphoblastic leukemia patients. Pharmacogenomics. 2015; 16(10):1119-34. DOI: 10.2217/PGS.15.62. View

15.

Wahlund M, Nilsson A, Zimdahl Kahlin A, Broliden K, Hed Myrberg I, Appell M . The Role of TPMT, ITPA, and NUDT15 Variants during Mercaptopurine Treatment of Swedish Pediatric Patients with Acute Lymphoblastic Leukemia. J Pediatr. 2019; 216:150-157.e1. DOI: 10.1016/j.jpeds.2019.09.024. View

16.

Lopez-Lopez E, Gutierrez-Camino A, Bilbao-Aldaiturriaga N, Pombar-Gomez M, Martin-Guerrero I, Garcia-Orad A . Pharmacogenetics of childhood acute lymphoblastic leukemia. Pharmacogenomics. 2014; 15(10):1383-98. DOI: 10.2217/pgs.14.106. View

17.

Relling M, Schwab M, Whirl-Carrillo M, Suarez-Kurtz G, Pui C, Stein C . Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. Clin Pharmacol Ther. 2018; 105(5):1095-1105. PMC: 6576267. DOI: 10.1002/cpt.1304. View

18.

Pui C, Cheng C, Leung W, Rai S, Rivera G, Sandlund J . Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N Engl J Med. 2003; 349(7):640-9. DOI: 10.1056/NEJMoa035091. View

19.

Kerb R, Brinkmann U, Chatskaia N, Gorbunov D, Gorboulev V, Mornhinweg E . Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics. 2002; 12(8):591-5. DOI: 10.1097/00008571-200211000-00002. View

20.

Carvalho D, Wanderley A, Dos Santos A, Fernandes M, Castro A, Leitao L . Pharmacogenomics and variations in the risk of toxicity during the consolidation/maintenance phases of the treatment of pediatric B-cell leukemia patients from an admixed population in the Brazilian Amazon. Leuk Res. 2018; 74:10-13. DOI: 10.1016/j.leukres.2018.09.003. View