Prevalence of NUDT15c.415C>T and ITPAc.94C>A among Thai pediatric patients with acute lymphoblastic leukemia using simultaneous multiplex ARMS PCR
Keywords:
ITPAc.94C>A, NUDT15 c.415C>T, Acute lymphoblastic leukemia, 6-mercaptopurine, multiplex ARMS PCRAbstract
Introduction: Nucleoside diphosphate-linked moiety X-type motif 15 c.415C>T (NUDT15c.415C>T) and inosine triphosphate pyrophosphatase c.94C>A (ITPAc.94C>A) are associated with a decreased degradation of 6-mercaptopurine (6-MP) among patients with acute lymphoblastic leukemia (ALL), resulting in a risk of bone marrow cytotoxicity (myelotoxicity). Objective: The study aimed to investigate the prevalence of NUDT15c.415C>T and ITPAc.94C>A genes among pediatric patients with ALL at Siriraj Hospital for surveillance of 6-MP-related side effects. Material and Methods: Sample specimens were collected from 222 pediatric patients and analyzed using a multiplex ARMS PCR method that was developed to detect the polymorphism of NUDT15c.415C>T and ITPAc.94C>A in a single detection. Results: The proportions of homozygous NUDT15c.415C>T and ITPAc.94C>A were 0.90 and 4.50%, respectively, while the proportions of heterozygous NUDT15c.415C>T and ITPAc.94C>A were 13.10 and 29.70%, respectively. The proportions of those harboring both the NUDT15c.415C>T and ITPAc.94C>A alleles were 5.40, and 0.90% of all patients harboring the heterozygous genetic pattern of one gene and homozygous for another gene. The proportion of those with wild-type genotypes of both genes was 45.50%. Co-occurrence of the homozygous genotype in both genes was not found in this cohort. In addition, the allele frequencies of NUDT15c.415C>T and ITPAc.94C>A were 10.81, and 22.70% respectively. Conclusion: The genetic polymorphism of ITPAc.94C>A appeared to be more prevalent than that of NUDT15c.415C>T among Thai pediatric patients with ALL. Interestingly, in this case, the heterozygous genetic pattern of one gene was related to the homozygous of another gene. Further studies are warranted to elucidate the clinical significance of ITPAc.94C>A on myelotoxicity among Thai pediatric patients treated with thiopurine. Furthermore, this method offers time-efficient and economic advantages as it can evaluate both polymorphism in a single procedure.
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Wu C, Li W. Genomics and pharmacogenomics of pediatric acute lymphoblastic leukemia. Crit Rev Oncol Hematol. 2018;126:100-11.
Schmiegelow K, Nielsen SN, Frandsen TL, Nersting J. Mercaptopurine/Methotrexate maintenance therapy of childhood acute lymphoblastic leukemia: clinical facts and fiction. J Pediatr Hematol Oncol. 2014;36:503-17.
Rudin S, Marable M, Huang RS. The Promise of Pharmacogenomics in Reducing Toxicity During Acute Lymphoblastic Leukemia Maintenance Treatment. Genomics Proteomics Bioinformatics. 2017;15:82-93.
Srimartpirom S, Tassaneeyakul W, Kukongviriyapan V, Tassaneeyakul W. Thiopurine S-methyltransferase genetic polymorphism in the Thai population. Br J Clin Pharmacol. 2004;58:66-70.
Chang JG, Lee LS, Chen CM, Shih MC, Wu MC, Tsai FJ, et al. Molecular analysis of thiopurine S-methyltransferase alleles in South-east Asian populations. Pharmacogenetics. 2002;12:191-5.
Khera S, Trehan A, Bhatia P, Singh M, Bansal D, Varma N. Prevalence of TPMT, ITPA and NUDT 15 genetic polymorphisms and their relation to 6MP toxicity in north Indian children with acute lymphoblastic leukemia. Cancer Chemotherapy and Pharmacology. 2019;83:341-8.
Marsh S, King CR, Ahluwalia R, McLeod HL. Distribution of ITPA P32T alleles in multiple world populations. Journal of Human Genetics. 2004;49 :579-81.
Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol. 2015;33:1235-42.
Relling MV, Schwab M, Whirl-Carrillo M, Suarez-Kurtz G, Pui CH, Stein CM, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. Clin Pharmacol Ther. 2019;105:1095-105.
Moradveisi B, Muwakkit S, Zamani F, Ghaderi E, Mohammadi E, Zgheib NK. ITPA, TPMT, and NUDT15 genetic polymorphisms predict 6-mercaptopurine toxicity in Middle Eastern children with acute lymphoblastic leukemia. Frontiers in pharmacology. 2019;10:916.
Wang D-S, Yu C-H, Lin C-Y, Chang Y-H, Lin K-H, Lin D-T, et al. Childhood acute lymphoblastic leukemia mercaptopurine intolerance is associated with NUDT15 variants. Pediatric Research. 2021;89:217-22.
Wahlund M, Nilsson A, Kahlin AZ, Broliden K, Myrberg IH, Appell ML, et al. The role of TPMT, ITPA, and NUDT15 variants during mercaptopurine treatment of Swedish pediatric patients with acute lymphoblastic leukemia. The Journal of Pediatrics. 2020;216:150-7. e1.
Skrzypczak-Zielinska M, Borun P, Bartkowiak-Kaczmarek A, Zakerska-Banaszak O, Walczak M, Dobrowolska A, et al. A simple method for TPMT and ITPA genotyping using multiplex HRMA for patients treated with thiopurine drugs. Molecular Diagnosis & Therapy. 2016;20:493-9.
Miller S, DD D. Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.
Wan Rosalina W, Teh L, Mohamad N, Nasir A, Yusoff R, Baba A, et al. Polymorphism of ITPA 94C> A and risk of adverse effects among patients with acute lymphoblastic leukaemia treated with 6‐mercaptopurine. Journal of clinical pharmacy and therapeutics. 2012;37:237-41.
Shah SA, Paradkar M, Desai D, Ashavaid TF. Nucleoside diphosphate‐linked moiety X‐type motif 15 C415T variant as a predictor for thiopurine‐induced toxicity in Indian patients. Journal of gastroenterology and hepatology. 2017;32:620-4.
Bielinski SJ, Olson JE, Pathak J, Weinshilboum RM, Wang L, Lyke KJ, et al., editors. Preemptive genotyping for personalized medicine: design of the right drug, right dose, right time—using genomic data to individualize treatment protocol. Mayo Clinic Proceedings; 2014: Elsevier.
Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. Journal of the National Cancer Institute. 1999;91:2001-8.
Chiengthong K, Ittiwut C, Muensri S, Sophonphan J, Sosothikul D, Seksan P, et al. NUDT15 c.415C>T increases risk of 6-mercaptopurine induced myelosuppression during maintenance therapy in children with acute lymphoblastic leukemia. Haematologica. 2016;101:e24-6.
Buaboonnam J, Sripatanatadasakul P, Treesucon A, Glomglao W, Siraprapapat P, Narkbunnam N, et al. Effect of NUDT 15 on incidence of neutropenia in children with acute lymphoblastic leukemia. Pediatrics International. 2019;61:754-8.
Puangpetch A, Tiyasirichokchai R, Pakakasama S, Wiwattanakul S, Anurathapan U, Hongeng S, et al. NUDT15 genetic variants are related to thiopurine-induced neutropenia in Thai children with acute lymphoblastic leukemia. Pharmacogenomics. 2020;21:403-10.
Boonyawat B, Monsereenusorn C, Photia A, Lertvivatpong N, Kaewchaivijit V, Jindatanmanusan P, et al. ITPA:c.94C>A and NUDT15:c.415C>T Polymorphisms and their Relation to Mercaptopurine-Related Myelotoxicity in Childhood Leukemia in Thailand. Appl Clin Genet. 2021;14:341-51.
Khaeso K, Komvilaisak P, Chainansamit SO, Nakkam N, Suwannaying K, Kuwatjanakul P, et al. NUDT15 is a key genetic factor for prediction of hematotoxicity in pediatric patients who received a standard low dosage regimen of 6-mercaptopurine. Drug Metab Pharmacokinet. 2022;43:100436.
Svasdisant P, Glomglao W, Siraprapapat P, Inthararujikul W, Tachavanich K, Boonthimat C, et al. ITPA Polymorphisms and the Incidence of Toxicities in Children with Acute Lymphoblastic Leukemia. Mediterr J Hematol Infect Dis. 2023;15:e2023024.
Sumi S, Marinaki AM, Arenas M, Fairbanks L, Shobowale-Bakre M, Rees DC, et al. Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency. Human genetics. 2002;111:360-7.
Zelinkova Z, Derijks LJ, Stokkers PC, Vogels EW, van Kampen AH, Curvers WL, et al. Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression. Clinical Gastroenterology and Hepatology. 2006;4:44-9.
Stocco G, Cheok M, Crews K, Dervieux T, French D, Pei D, et al. Genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia. Clinical Pharmacology & Therapeutics. 2009;85:164-72.
Tanaka Y, Manabe A, Nakadate H, Kondoh K, Nakamura K, Koh K, et al. The activity of the inosine triphosphate pyrophosphatase affects toxicity of 6-mercaptopurine during maintenance therapy for acute lymphoblastic leukemia in Japanese children. Leukemia research. 2012;36:560-4.
Kim H, Kang HJ, Kim HJ, Jang MK, Kim NH, Oh Y,et al. Pharmacogenetic analysis of pediatric patients with acute lymphoblastic leukemia: a possible association between survival rate and ITPA polymorphism. PLoS One. 2012;7:e45558
Maeda T, Sumi S, Ueta A, Ohkubo Y, Ito T, Marinaki AM, et al. Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency in the Japanese population. Molecular genetics and metabolism. 2005;85:271-9.
Zhou H, Li L, Yang P, Yang L, Zheng JE, Zhou Y, et al. Optimal predictor for 6-mercaptopurine intolerance in Chinese children with acute lymphoblastic leukemia: NUDT15, TPMT, or ITPA genetic variants? BMC cancer. 2018;18:1-9.
Yang S-K, Hong M, Baek J, Choi H, Zhao W, Jung Y, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nature genetics. 2014;46:1017-20.
Tanaka Y, Kato M, Hasegawa D, Urayama KY, Nakadate H, Kondoh K, et al. Susceptibility to 6‐MP toxicity conferred by a NUDT 15 variant in Japanese children with acute lymphoblastic leukaemia. British journal of haematology. 2015;171:109-15.
Liang DC, Yang CP, Liu HC, Jaing TH, Chen SH, Hung IJ, et al. NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia. The Pharmacogenomics Journal. 2016;16:536-9.
Texis T, Guzmán-Cruz C, Rodríguez-Dorantes M, Sánchez-García S, Mino-León D, Gonzalez-Covarrubias V. Genotyping NUDT15*3 rs1166855232 reveals higher frequency of potential adverse effects of thiopurines in Natives and Mestizos from Mexico. Pharmacological Reports. 2022;74:257-62.
Matsuoka K. NUDT15 gene variants and thiopurine-induced leukopenia in patients with inflammatory bowel disease. Intestinal research. 2020;18:275.
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