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Jarrar Y, Ghishan M, Khirfan F, Hakooz N. Genetic variants in NUDT15 gene their clinical implications in cancer therapy. Drug Metab Pers Ther 2025:dmdi-2025-0003. [PMID: 40219790 DOI: 10.1515/dmpt-2025-0003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Accepted: 03/18/2025] [Indexed: 04/14/2025]
Abstract
Individual variations in the response to thiopurine-based anticancer drugs are influenced by genetic and environmental factors, making it challenging to optimize dosing and minimize toxicity. Among the key genes involved, genetic variations in the nudix hydrolase 15 (NUDT15) gene affect on thiopurine metabolism, thus influencing drug efficacy and the risk of severe adverse effects, such as myelosuppression, These variations also contribute to inter-individual differences in drug tolerance and clinical outcomes. Despite the recognized impact of NUDT15 variations, there has been limited comprehensive exploration of these variants and their clinical significance in thiopurine therapy. This review provides a thorough analysis of NUDT15 genetic variants by synthesizing findings from prior clinical studies and employing in silico analyses to predict the functional effects of variants with uncertain significance. Comprehensive analysis of NUDT15 variants and their interactions with other metabolic pathways could offer valuable insights for advancing personalized medicine in cancer treatment. This review aims to establish a foundation for integrating NUDT15 genetic information into the clinical practice, reducing toxicity, and improved therapeutic outcomes in patients undergoing thiopurine-based chemotherapy.
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Affiliation(s)
- Yazun Jarrar
- Department of Basic Medical Sciences, Faculty of Medicine, Al-Balqa Applied University, Al-Salt, Jordan
| | - Maria Ghishan
- Department of Pharmaceutical Science, College of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan
| | - Fatima Khirfan
- Department of Pharmaceutical Science, College of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan
| | - Nancy Hakooz
- School of Pharmacy, The University of Jordan, Amman, Jordan
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2
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Tanaka Y, Ono R, Ashiarai M, Sakurai A, Watanabe A, Tsuchimochi T, Hosoya Y, Hanajiri R, Inukai T, Hasegawa D. The evaluation of the impact of NUDT15 variants on thiopurine metabolism in Japanese children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol 2025; 95:50. [PMID: 40169418 DOI: 10.1007/s00280-025-04774-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 03/18/2025] [Indexed: 04/03/2025]
Abstract
PURPOSE This study aimed to evaluate the impact of Nudix hydrolase 15 (NUDT15) variants on thiopurine metabolites, DNA-incorporated thioguanine nucleotides (DNA-TG), erythrocyte thioguanine nucleotides (Ery-TGNs) and methyl mercaptopurine nucleotide (Ery-MMPN) levels, and the association among the levels of these 6-MP metabolites in Japanese children with acute lymphoblastic leukemia (ALL). METHODS DNA-TG, Ery-TGNs, and Ery-MMPN levels were measured in 20 Japanese patients with childhood ALL (171 sampling points) on consecutive clinical visits, using liquid chromatography with tandem mass spectrometry. NUDT15 was genotyped using Sanger sequencing. RESULTS Three NUDT15 intermediate metabolizers (IM, *1/*2 or *1/*3) and two poor metabolizers (PM, *3/*3) were identified. DNA-TG/dose was significantly higher in PM than in normal metabolizers (NM). Intra-patient coefficients of variation (CV) of DNA-TG levels were similar in NUDT15 genotypes, and inter-patient CV was higher in IM and PM than in NM. The DNA-TG/Ery-TGNs ratio was higher in IM and PM than in NM (p < 0.01). The ranges of DNA-TG/dose and DNA-TG/Ery-TGNs ratio were not different within NUDT15 phenotypes. In NUDT15 NM, patients with high Ery-TGNs/dose showed high DNA-TG/dose. Absolute lymphocyte count was significantly correlated with DNA-TG, Ery-TGNs, and Ery-MMPN levels (p < 0.001). White blood cell counts were significantly correlated with Ery-TGNs levels (p < 0.02), and the levels of aspartate and alanine aminotransferases were significantly correlated with Ery-MMPN levels (p < 0.001). CONCLUSION NUDT15 phenotype is a strong factor for thiopurine trialability in Japanese children with ALL. Ery-TGNs levels may associate with difference of individual response.
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Affiliation(s)
- Yoichi Tanaka
- Division of Medicinal Safety Science, National Institute of Health Sciences, Kanagawa, Japan.
| | - Rintaro Ono
- Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan
| | - Miho Ashiarai
- Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan
| | - Ayako Sakurai
- Department of Pediatrics, Japanese Red Cross Narita Hospital, Chiba, Japan
| | - Atsushi Watanabe
- Department of Pediatrics, University of Yamanashi, Yamanashi, Japan
- Department of Pediatrics, Yamanashi Prefectural Central Hospital, Yamanashi, Japan
| | | | - Yosuke Hosoya
- Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan
| | - Ruri Hanajiri
- Division of Medicinal Safety Science, National Institute of Health Sciences, Kanagawa, Japan
| | - Takeshi Inukai
- Department of Pediatrics, University of Yamanashi, Yamanashi, Japan
| | - Daisuke Hasegawa
- Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan
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Maillard M, Nguyen JQ, Yang W, Hoshitsuki K, Relling MV, Caudle KE, Crews KR, Jeha S, Inaba H, Pui CH, Bhatia S, Karol SE, Antillon-Klussmann FG, Haidar CE, Bhojwani D, Yang JJ. Clinical Actionability of the NUDT15 *4 (p.R139H) Allele and Its Association With Hispanic Ethnicity. Clin Pharmacol Ther 2025; 117:724-731. [PMID: 39688234 PMCID: PMC11995662 DOI: 10.1002/cpt.3501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 11/10/2024] [Indexed: 12/18/2024]
Abstract
Nudix hydrolase 15 (NUDT15) deficiency is strongly associated with thiopurine-induced myelosuppression. Currently, testing for NUDT15 deficiency is based on the genotyping of the most frequent and clinically characterized no-function variants, that is, *2, *3 and *9. The Hispanic/Latino-predominant variant NUDT15 *4 (p.R139H) is classified as "uncertain function" by the Clinical Pharmacogenetics Implementation Consortium, because of insufficient data to ascertain its clinical actionability. In this study, we evaluated the association of NUDT15 *4 with mercaptopurine (6-MP) tolerance in a retrospective cohort of 1,399 patients with acute lymphoblastic leukemia (ALL) of diverse ancestries. All patients were wildtype for thiopurine methyltransferase gene. Patients were treated with 6-MP in the context of ALL frontline clinical trials. The tolerated dose of 6-MP was used to assess drug toxicity during the maintenance phase of ALL therapy. Patients with NUDT15 *1/*4 (n = 16, all of whom self-identified as Hispanic/Latino) tolerated a significantly lower dose of 6-MP than did those with NUDT15 *1/*1: median [interquartile range] of 39.0 [21.2-52.8] mg/m2, vs. 62.2 [47.9-71.6] mg/m2, P value < 0.001. No patient homozygous for *4 was detected. In a separate retrospective validation study, six patients were identified as having NUDT15 *1/*4 by routine clinical pharmacogenetics testing and tolerated a 6-MP median dose of 38.7 mg/m2 (IQR, 33.7-54.0), confirming the need for dose reduction attributed to the NUDT15 *4 variant. These results point to the need to include NUDT15 *4 in pharmacogenetics-guided thiopurine dosing algorithms.
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Affiliation(s)
- Maud Maillard
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Jenny Q. Nguyen
- Personalized Care Program, Children’s Hospital Los Angeles, Los Angeles, California, USA
| | - Wenjian Yang
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Keito Hoshitsuki
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Mary V. Relling
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Kelly E. Caudle
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Kristine R. Crews
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Sima Jeha
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
- Department of Global Pediatric Medicine, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Hiroto Inaba
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Ching-Hon Pui
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
- Department of Global Pediatric Medicine, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Smita Bhatia
- Institute for Cancer Outcomes and Survivorship and Division of Pediatric Hematology-Oncology, University of Alabama at Birmingham, Alabama, USA
| | - Seth E. Karol
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | | | - Cyrine E. Haidar
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Deepa Bhojwani
- Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Jun J. Yang
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
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4
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Belardi R, Pacifici F, Baldetti M, Velocci S, Minieri M, Pieri M, Campione E, Della-Morte D, Tisone G, Anselmo A, Novelli G, Bernardini S, Terrinoni A. Trends in Precision Medicine and Pharmacogenetics as an Adjuvant in Establishing a Correct Immunosuppressive Therapy for Kidney Transplant: An Up-to-Date Historical Overview. Int J Mol Sci 2025; 26:1960. [PMID: 40076585 PMCID: PMC11900248 DOI: 10.3390/ijms26051960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/17/2025] [Accepted: 02/20/2025] [Indexed: 03/14/2025] Open
Abstract
Kidney transplantation is currently the treatment of choice for patients with end-stage kidney diseases. Although significant advancements in kidney transplantation have been achieved over the past decades, the host's immune response remains the primary challenge, often leading to potential graft rejection. Effective management of the immune response is essential to ensure the long-term success of kidney transplantation. To address this issue, immunosuppressives have been developed and are now fully integrated into the clinical management of transplant recipients. However, the considerable inter- and intra-patient variability in pharmacokinetics (PK) and pharmacodynamics (PD) of these drugs represents the primary cause of graft rejection. This variability is primarily attributed to the polymorphic nature (genetic heterogeneity) of genes encoding xenobiotic-metabolizing enzymes, transport proteins, and, in some cases, drug targets. These genetic differences can influence drug metabolism and distribution, leading to either toxicity or reduced efficacy. The main objective of the present review is to report an historical overview of the pharmacogenetics of immunosuppressants, shedding light on the most recent findings and also suggesting how relevant is the research and investment in developing validated NGS-based commercial panels for pharmacogenetic profiling in kidney transplant recipients. These advancements will enable the implementation of precision medicine, optimizing immunosuppressive therapies to improve graft survival and kidney transplanted patient outcomes.
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Affiliation(s)
- Riccardo Belardi
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
| | - Francesca Pacifici
- Department of Human Sciences and Quality of Life Promotion, San Raffaele University, 00166 Rome, Italy; (F.P.); (D.D.-M.)
- Interdisciplinary Center for Advanced Studies on Lab-on-Chip and Organ-on-Chip Applications (ICLOC), University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Matteo Baldetti
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
| | - Silvia Velocci
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
| | - Marilena Minieri
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
| | - Massimo Pieri
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
| | - Elena Campione
- Dermatology Unit, Policlinico Tor Vergata, System Medicine Department, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | - David Della-Morte
- Department of Human Sciences and Quality of Life Promotion, San Raffaele University, 00166 Rome, Italy; (F.P.); (D.D.-M.)
- Interdisciplinary Center for Advanced Studies on Lab-on-Chip and Organ-on-Chip Applications (ICLOC), University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
- Department of Neurology, Evelyn F. McKnight Brain Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | - Giuseppe Tisone
- Department of Surgery, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (G.T.)
| | - Alessandro Anselmo
- Department of Surgery, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (G.T.)
| | - Giuseppe Novelli
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | - Sergio Bernardini
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
| | - Alessandro Terrinoni
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
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Shaaban S, Walker BS, Ji Y, Johnson-Davis K. TPMT and NUDT15 genotyping, TPMT enzyme activity and metabolite determination for thiopurines therapy: a reference laboratory experience. Pharmacogenomics 2025; 25:679-688. [PMID: 39957149 PMCID: PMC11901404 DOI: 10.1080/14622416.2025.2463866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 02/04/2025] [Indexed: 02/18/2025] Open
Abstract
AIM To share the experience of a US national reference laboratory, offering genotyping for TPMT and NUDT15, TPMT enzyme phenotyping and detection of thiopurine metabolites. METHODS Retrospective review of archived datasets related to thiopurines drug therapy including patients' data that underwent TPMT and NUDT15 genotyping, and smaller data sets where genotyping was performed with TPMT enzyme levels (phenotyping) +/- therapeutic drug monitoring (TDM). RESULTS Thirteen percent of patients had variants in one or both genes tested. Testing for NUDT15 revealed 3.9% additional patients requiring thiopurines dosing recommendations. A correlation between TPMT enzyme activity and TPMT polymorphisms (odds ratio OD = 71.41, p-value <0.001) and between older age and higher enzyme levels (OD = 0.98, p-value = 0.002) was identified. No correlation between sex and TPMT enzyme levels, nor between TPMT genotyping and the level of thiopurine metabolites was found. CONCLUSION Adding NUDT15 to TPMT genotyping, identified additional 3.9% patients to benefit from thiopurine dose modifications. A significant correlation between genetic variants in TPMT and TPMT enzyme levels and between age and enzyme levels was established, while no correlation was identified between sex and enzyme levels nor between TPMT variation and thiopurine metabolites. Providers rely more significantly on genotyping only approach, rather than genotyping and phenotyping.
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Affiliation(s)
- Sherin Shaaban
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA
- ARUP Laboratories, Salt Lake City, UT, USA
| | | | - Yuan Ji
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA
- ARUP Laboratories, Salt Lake City, UT, USA
| | - Kamisha Johnson-Davis
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA
- ARUP Laboratories, Salt Lake City, UT, USA
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Coelho T, Cheng G, Lewis S, Ashton JJ, Barakat F, Driscoll KCT, Sholeye-Bolaji AE, Batra A, Afzal NA, Beattie RM, Ennis S. Pharmacogenomic Assessment of Genes Implicated in Thiopurine Metabolism and Toxicity in a UK Cohort of Pediatric Patients With Inflammatory Bowel Disease. Inflamm Bowel Dis 2025; 31:362-375. [PMID: 39011784 DOI: 10.1093/ibd/izae126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Indexed: 07/17/2024]
Abstract
BACKGROUND Thiopurine drugs are effective treatment options in inflammatory bowel disease and other conditions but discontinued in some patients due to toxicity. METHODS We investigated thiopurine-induced toxicity in a pediatric inflammatory bowel disease cohort by utilizing exome sequencing data across a panel of 46 genes, including TPMT and NUDT15. RESULTS The cohort included 487 patients with a median age of 13.1 years. Of the 396 patients exposed to thiopurines, myelosuppression was observed in 11%, gastroenterological intolerance in 11%, hepatotoxicity in 4.5%, pancreatitis in 1.8%, and "other" adverse effects in 2.8%. TPMT (thiopurine S-methyltransferase) enzyme activity was normal in 87.4%, intermediate 12.3%, and deficient in 0.2%; 26% of patients with intermediate activity developed toxicity to thiopurines. Routinely genotyped TPMT alleles associated with defective enzyme activity were identified in 28 (7%) patients: TPMT*3A in 4.5%, *3B in 1%, and *3C in 1.5%. Of these, only 6 (21%) patients developed toxic responses. Three rare TPMT alleles (*3D, *39, and *40) not assessed on routine genotyping were identified in 3 patients, who all developed toxic responses. The missense variant p.R139C (NUDT15*3 allele) was identified in 4 patients (azathioprine 1.6 mg/kg/d), but only 1 developed toxicity. One patient with an in-frame deletion variant p.G13del in NUDT15 developed myelosuppression at low doses. Per-gene deleteriousness score GenePy identified a significant association for toxicity in the AOX1 and DHFR genes. CONCLUSIONS A significant association for toxicity was observed in the AOX1 and DHFR genes in individuals negative for the TPMT and NUDT15 variants. Patients harboring the NUDT15*3 allele, which is associated with myelosuppression, did not show an increased risk of toxicity.
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Affiliation(s)
- Tracy Coelho
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
| | - Guo Cheng
- Human Genetics and Genomic Medicine, University of Southampton, Southampton, United Kingdom
| | - Sophie Lewis
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
| | - James J Ashton
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
- Human Genetics and Genomic Medicine, University of Southampton, Southampton, United Kingdom
| | - Farah Barakat
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
| | - Kouros C T Driscoll
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
| | - Adebola E Sholeye-Bolaji
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
| | - Akshay Batra
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
| | - Nadeem A Afzal
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
| | - Robert M Beattie
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
| | - Sarah Ennis
- Human Genetics and Genomic Medicine, University of Southampton, Southampton, United Kingdom
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7
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Fuerte B, Burgos M, Cao V, Maggo S, Bhojwani D, Rushing T, Nguyen JQ, Gong CL. Budget impact analysis of TPMT and NUDT15 pharmacogenomic testing for 6-mercaptopurine in pediatric acute lymphoblastic leukemia patients. Pharmacogenet Genomics 2025; 35:73-80. [PMID: 39470342 DOI: 10.1097/fpc.0000000000000550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/30/2024]
Abstract
BACKGROUND Pharmacogenomic testing identifies gene polymorphisms impacting drug metabolism, aiding in optimizing treatment efficacy and minimizing toxicity, thus potentially reducing healthcare utilization. 6-Mercaptopurine metabolism is affected by thiopurine methyltransferase ( TPMT ) and nudix hydrolase 15 ( NUDT15 ) polymorphisms. We sought to estimate the budget impact of preemptive pharmacogenomic testing for these genes in pediatric acute lymphoblastic leukemia (ALL) patients from an institutional perspective. METHODS A Markov model was constructed to model the first cycle of the maintenance phase of chemotherapy for pediatric ALL patients transitioning between one of three health states: stable, moderately myelosuppressed, and severely myelosuppressed over 16 weeks, with each health state's associated costs derived from the literature. The patient's likelihood to experience moderate or severe myelosuppression based on metabolism phenotype was calculated from the literature and applied on a weekly basis, and the marginal budget impact of preemptive pharmacogenomic testing vs. no pharmacogenomic testing was calculated. One-way sensitivity analysis was conducted to assess parameter influence on results. RESULTS Preemptive pharmacogenomic testing of TPMT and NUDT15 provided savings of up to $26 028 per patient during the maintenance phase. In the sensitivity analysis, the cost of outpatient management of moderate myelosuppression had the greatest impact on the budget, resulting in cost savings ranging from $8592 to $30 129 when the minimum and maximum costs of management were used in the model. CONCLUSION Preemptive pharmacogenomic testing for TPMT and NUDT15 polymorphisms before initiation of maintenance therapy for pediatric ALL patients yielded considerable cost savings.
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Affiliation(s)
- Beverly Fuerte
- Department of Pharmacy, Alfred E. Mann School of Pharmacy, University of Southern California, Los Angeles, California
| | - Mia Burgos
- Department of Pharmacy, Alfred E. Mann School of Pharmacy, University of Southern California, Los Angeles, California
| | - Vyvy Cao
- Department of Pharmacy, Alfred E. Mann School of Pharmacy, University of Southern California, Los Angeles, California
| | - Simran Maggo
- Department of Pharmacy, Bernard J. Dunn School of Pharmacy, Shenandoah University, Winchester, Virginia
| | - Deepa Bhojwani
- Department of Pediatrics, Cancer and Blood Disease Institute, Children's Hospital Los Angeles, and Keck School of Medicine, University of Southern California
| | | | - Jenny Q Nguyen
- Personalized Care Program, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles
| | - Cynthia L Gong
- Division of Neonatology, Department of Pediatrics, Fetal and Neonatal Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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8
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Kennedy AM, Griffiths AM, Muise AM, Walters TD, Ricciuto A, Huynh HQ, Wine E, Jacobson K, Lawrence S, Carman N, Mack DR, deBruyn JC, Otley AR, Deslandres C, El-Matary W, Zachos M, Benchimol EI, Critch J, Schneider R, Crowley E, Li M, Warner N, McGovern DPB, Li D, Haritunians T, Rudin S, Cohn I. Landscape of TPMT and NUDT15 Pharmacogenetic Variation in a Cohort of Canadian Pediatric Inflammatory Bowel Disease Patients. Inflamm Bowel Dis 2024; 30:2418-2427. [PMID: 38788739 PMCID: PMC11630297 DOI: 10.1093/ibd/izae109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Indexed: 05/26/2024]
Abstract
BACKGROUND Patients with inflammatory bowel disease (IBD) exhibit considerable interindividual variability in medication response, highlighting the need for precision medicine approaches to optimize and tailor treatment. Pharmacogenetics (PGx) offers the ability to individualize dosing by examining genetic factors underlying the metabolism of medications such as thiopurines. Pharmacogenetic testing can identify individuals who may be at risk for thiopurine dose-dependent adverse reactions including myelosuppression. We aimed to evaluate PGx variation in genes supported by clinical guidelines that inform dosing of thiopurines and characterize differences in the distribution of actionable PGx variation among diverse ancestral groups. METHODS Pharmacogenetic variation in TPMT and NUDT15 was captured by genome-wide genotyping of 1083 pediatric IBD patients from a diverse Canadian cohort. Genetic ancestry was inferred using principal component analysis. The proportion of PGx variation and associated metabolizer status phenotypes was compared across 5 genetic ancestral groups within the cohort (Admixed American, African, East Asian, European, and South Asian) and to prior global estimates from corresponding populations. RESULTS Collectively, 11% of the cohort was categorized as intermediate or poor metabolizers of thiopurines, which would warrant a significant dose reduction or selection of alternate therapy. Clinically actionable variation in TPMT was more prevalent in participants of European and Admixed American/Latino ancestry (8.7% and 7.5%, respectively), whereas variation in NUDT15 was more prevalent in participants of East Asian and Admixed American/Latino ancestry (16% and 15% respectively). CONCLUSIONS These findings demonstrate the considerable interpopulation variability in PGx variation underlying thiopurine metabolism, which should be factored into testing diverse patient populations.
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Affiliation(s)
- April M Kennedy
- Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Anne M Griffiths
- SickKids IBD Centre, Division of Gastroenterology, Hepatology & Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada
- Child Health Evaluative Sciences, SickKids Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Aleixo M Muise
- SickKids IBD Centre, Division of Gastroenterology, Hepatology & Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
- Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
- Cell Biology Program, SickKids Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Thomas D Walters
- SickKids IBD Centre, Division of Gastroenterology, Hepatology & Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Amanda Ricciuto
- SickKids IBD Centre, Division of Gastroenterology, Hepatology & Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada
- Child Health Evaluative Sciences, SickKids Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Hien Q Huynh
- Edmonton Pediatric IBD Clinic, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Eytan Wine
- Edmonton Pediatric IBD Clinic, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Kevan Jacobson
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Sally Lawrence
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Nicholas Carman
- SickKids IBD Centre, Division of Gastroenterology, Hepatology & Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - David R Mack
- CHEO IBD Centre, Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children’s Hospital of Eastern Ontario, CHEO Research Institute and Department of Pediatrics, University of Ottawa, Ottawa, Canada
| | - Jennifer C deBruyn
- Department of Pediatrics, Alberta Children’s Hospital Research Institute (ACHRI), University of Calgary, Calgary, Alberta, Canada
| | - Anthony R Otley
- Division of Pediatric Gastroenterology & Nutrition, Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Colette Deslandres
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montréal, Quebec, Canada
| | - Wael El-Matary
- Section of Pediatric Gastroenterology, Winnipeg Children’s Hospital, University of Manitoba, Winnipeg, MB, Canada
| | - Mary Zachos
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
| | - Eric I Benchimol
- SickKids IBD Centre, Division of Gastroenterology, Hepatology & Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada
- Child Health Evaluative Sciences, SickKids Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - Jeffrey Critch
- Faculty of Medicine, Memorial University, St John’s, Newfoundland & Labrador, Canada
| | - Rilla Schneider
- Division of Gastroenterology and Nutrition, Department of Pediatrics, Montreal Children’s Hospital, Montreal, Quebec, Canada
| | - Eileen Crowley
- Department of Pediatrics, Division of Pediatric Gastroenterology & Hepatology, Children’s Hospital Western Ontario, Western University, London, Ontario, Canada
| | - Michael Li
- The Centre for Computational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Neil Warner
- Cell Biology Program, SickKids Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
- SickKids IBD Centre, Division of Gastroenterology, Hepatology & Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Dermot P B McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Dalin Li
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Talin Haritunians
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Sarah Rudin
- Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Iris Cohn
- Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
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9
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Zachman DK, Bardahl JG, Graves LA, Wagner LM. Impact of Duffy-associated neutrophil count on maintenance chemotherapy management in a child with acute lymphoblastic leukemia. Pediatr Blood Cancer 2024; 71:e31355. [PMID: 39323046 DOI: 10.1002/pbc.31355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 09/15/2024] [Indexed: 09/27/2024]
Affiliation(s)
- Derek K Zachman
- Division of Pediatric Hematology-Oncology, Duke University Medical Center, Durham, North Carolina, USA
| | - Jonathan G Bardahl
- Division of Pediatric Hematology-Oncology, Duke University Medical Center, Durham, North Carolina, USA
| | - Laurie A Graves
- Division of Pediatric Hematology-Oncology, Duke University Medical Center, Durham, North Carolina, USA
| | - Lars M Wagner
- Division of Pediatric Hematology-Oncology, Duke University Medical Center, Durham, North Carolina, USA
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10
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Deenen MJ, van Noordenburg AJ, Bouwens-Bijsterveld J, van Dijk MA, Stapelbroek JM, Derijks LJJ, Gilissen LPL, Deiman BALM. Genetic association analysis and frequency of NUDT15*3 with thiopurine-induced myelosuppression in patients with inflammatory bowel disease in a large Dutch cohort. THE PHARMACOGENOMICS JOURNAL 2024; 24:39. [PMID: 39580429 DOI: 10.1038/s41397-024-00358-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 10/29/2024] [Accepted: 11/13/2024] [Indexed: 11/25/2024]
Abstract
Thiopurine drugs are cornerstone treatment for patients with inflammatory bowel disease (IBD). The most common adverse drug reaction is thiopurine-induced myelosuppression (TIM), that may partly be explained by the genetic polymorphism NUDT15*3. The aim of this retrospective study was to determine the NUDT15*3 polymorphism frequency and its association with TIM in an IBD patient population in the Netherlands. DNA from patients previously genotyped for TPMT was genotyped for NUDT15*3. In IBD patients treated with thiopurines association tests with TIM were conducted. Out of 988 included patients, 13 (1.3%) were heterozygous for NUDT15*3. Of all patients, 606 had IBD and received thiopurine treatment. In these patients, 8/606 (1.3%) were heterozygous polymorphic for NUDT15*3 of which 50.0% developed TIM compared to 2.3% in the wild type patients (p < 0.001). The study results show a clinically relevant prevalence of NUDT15*3 in the Dutch patient population. Its strong association with TIM suggests pre-therapeutic genotyping potentially clinically utile.
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Affiliation(s)
- Maarten J Deenen
- Department of Clinical Pharmacy, Catharina Hospital, Eindhoven, the Netherlands.
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Centre, Leiden, the Netherlands.
| | | | | | - Maarten A van Dijk
- Department of Gastroenterology and Hepatology, Elkerliek Hospital, Helmond, the Netherlands
| | | | - Luc J J Derijks
- Department of Clinical Pharmacy, Máxima Medical Centre, Eindhoven, the Netherlands
- Department of Clinical Pharmacy & Toxicology, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Lennard P L Gilissen
- Department of Gastroenterology and Hepatology, Catharina Hospital, Eindhoven, the Netherlands
| | - Birgit A L M Deiman
- Department of Clinical Chemistry, Catharina Hospital, Eindhoven, the Netherlands
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11
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Ray A, Levitt M, Efunkoya T, Trinkman H. Precision Medicine for Acute Lymphoblastic Leukemia in Children: A Review. CHILDREN (BASEL, SWITZERLAND) 2024; 11:1329. [PMID: 39594904 PMCID: PMC11593090 DOI: 10.3390/children11111329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 10/26/2024] [Accepted: 10/29/2024] [Indexed: 11/28/2024]
Abstract
The clinical outcome for children diagnosed with acute lymphoblastic leukemia is a testimony to the success of modern medicine. Over the past few decades, survival has climbed from ∼10% to >90% for certain subgroups. Yet, the outcome for those with relapsed disease is often poor, and survivors struggle with a multitude of healthcare issues, some of which are lifelong. In recent years, the advent of the widespread sequencing of tumors has made available patients with previously unrecognized subtypes of leukemia, who have the potential to benefit from the addition of targeted therapies. Indeed, the promise of precision medicine, encompassing a person's environment, genetics and lifestyle, is likely to have profound impact on further tailoring therapies that are likely to improve outcomes, diminish toxicity and ultimately pave the pathway for a healthier population.
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Affiliation(s)
- Anish Ray
- Cook Children’s Medical Center, Fort Worth, TX 76104, USA; (T.E.); (H.T.)
| | - Michael Levitt
- University of North Texas Health Science Center, Texas College of Osteopathic Medicine, Fort Worth, TX 76107, USA;
| | | | - Heidi Trinkman
- Cook Children’s Medical Center, Fort Worth, TX 76104, USA; (T.E.); (H.T.)
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12
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Šmid A, Urbančič D, Žlajpah JV, Stollarova N, Prelog T, Kavčič M, Jazbec J, Mlinarič-Raščan I, Kuželički NK. Genetic profiling of NUDT15 in the Slovenian population. Pharmacogenomics 2024; 25:515-525. [PMID: 39453028 DOI: 10.1080/14622416.2024.2409060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 09/23/2024] [Indexed: 10/26/2024] Open
Abstract
Determining variant TPMT alleles to predict patient response to thiopurine therapy represents one of the first successful implementations of pharmacogenomics in clinical practice. However, despite the TPMT-adjusted thiopurine dosing, some TPMT wild-type patients still exhibit toxicity at standard doses. Over the past decade, the pharmacogene NUDT15 has emerged as a significant co-modulator of thiopurine therapy. Initially, NUDT15 was considered important predominantly in Asian populations, but recent studies have highlighted its relevance in European populations as well.To evaluate the pharmacogenetic significance of NUDT15 in the Slovenian population, we sequenced extended regions of exon 1 and exon 3 in 109 healthy individuals and 37 patients with acute lymphoblastic leukemia.We identified eight variants, including one with established clinical significance (allele *3) and one extremely rare variant (Chr13 at 48045861; GRCh38, NC_000013.11). The frequencies of most previously described variants in both the general population and in the ALL cohort were consistent with those reported in other European populations, except for rs45465203, which was less frequent in the Slovenian population. None of the variants, except for NUDT15*3, were associated with cumulative thiopurine doses in ALL patients. However, these variants warrant further investigation in larger ALL cohorts.
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Affiliation(s)
- Alenka Šmid
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, Ljubljana, 1000, Slovenia
| | - Dunja Urbančič
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, Ljubljana, 1000, Slovenia
| | - Jaka Vrevc Žlajpah
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, Ljubljana, 1000, Slovenia
| | - Natalia Stollarova
- Comenius University, Faculty of Pharmacy, Department of Pharmacology and Toxicology, Bratislava, 81499, Slovakia
| | - Tomaž Prelog
- University Medical Centre Ljubljana, University Children`s Hospital, Department of Pediatric Hematology and Oncology, Ljubljana, 1000, Slovenia
| | - Marko Kavčič
- University Medical Centre Ljubljana, University Children`s Hospital, Department of Pediatric Hematology and Oncology, Ljubljana, 1000, Slovenia
- University of Ljubljana, Faculty of Medicine, Ljubljana, 1000, Slovenia
| | - Janez Jazbec
- University Medical Centre Ljubljana, University Children`s Hospital, Department of Pediatric Hematology and Oncology, Ljubljana, 1000, Slovenia
- University of Ljubljana, Faculty of Medicine, Ljubljana, 1000, Slovenia
| | - Irena Mlinarič-Raščan
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, Ljubljana, 1000, Slovenia
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13
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Nogueiras-Álvarez R, Pérez Francisco I. Pharmacogenetics in Oncology: A useful tool for individualizing drug therapy. Br J Clin Pharmacol 2024; 90:2483-2508. [PMID: 39077855 DOI: 10.1111/bcp.16181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 06/28/2024] [Indexed: 07/31/2024] Open
Abstract
With the continuous development of genetics in healthcare, there has been a significant contribution to the development of precision medicine, which is ultimately aimed at improving the care of patients. Generally, drug treatments used in Oncology are characterized by a narrow therapeutic range and by their potential toxicity. Knowledge of pharmacogenomics and pharmacogenetics can be very useful in the area of Oncology, as they constitute additional tools that can help to individualize patients' treatment. This work includes a description of some genes that have been revealed to be useful in the field of Oncology, as they play a role in drug prescription and in the prediction of treatment response.
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Affiliation(s)
- Rita Nogueiras-Álvarez
- Osakidetza Basque Health Service, Galdakao-Usansolo University Hospital, Basque Country Pharmacovigilance Unit, Galdakao, Bizkaia/Vizcaya, Spain
| | - Inés Pérez Francisco
- Breast Cancer Research Group, Bioaraba Health Research Institute, Vitoria-Gasteiz, Araba/Álava, Spain
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14
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Bayoumy AB, Ansari AR, Mulder CJJ, Schmiegelow K, Florin T, De Boer NKH. Innovating Thiopurine Therapeutic Drug Monitoring: A Systematic Review and Meta-Analysis on DNA-Thioguanine Nucleotides (DNA-TG) as an Inclusive Biomarker in Thiopurine Therapy. Clin Pharmacokinet 2024; 63:1089-1109. [PMID: 39031224 PMCID: PMC11343975 DOI: 10.1007/s40262-024-01393-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2024] [Indexed: 07/22/2024]
Abstract
BACKGROUND AND OBJECTIVE Thioguanine (TG), azathioprine (AZA), and mercaptopurine (MP) are thiopurine prodrugs commonly used to treat diseases, such as leukemia and inflammatory bowel disease (IBD). 6-thioguanine nucleotides (6-TGNs) have been commonly used for monitoring treatment. High levels of 6-TGNs in red blood cells (RBCs) have been associated with leukopenia, the cutoff levels that predict this side effect remain uncertain. Thiopurines are metabolized and incorporated into leukocyte DNA. Measuring levels of DNA-incorporated thioguanine (DNA-TG) may be a more suitable method for predicting clinical response and toxicities such as leukopenia. Unfortunately, most methodologies to assay 6-TGNs are unable to identify the impact of NUDT15 variants, effecting mostly ethnic populations (e.g., Chinese, Indian, Malay, Japanese, and Hispanics). DNA-TG tackles this problem by directly measuring thioguanine in the DNA, which can be influenced by both TPMT and NUDT15 variants. While RBC 6-TGN concentrations have traditionally been used to optimize thiopurine therapy due to their ease and affordability of measurement, recent developments in liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques have made measuring DNA-TG concentrations in lymphocytes accurate, reproducible, and affordable. The objective of this systematic review was to assess the current evidence of DNA-TG levels as marker for thiopurine therapy, especially with regards to NUDT15 variants. METHODS A systematic review and meta-analysis were performed on the current evidence for DNA-TG as a marker for monitoring thiopurine therapy, including methods for measurement and the illustrative relationship between DNA-TG and various gene variants (such as TPMT, NUDT15, ITPA, NT5C2, and MRP4). PubMed and Embase were systematically searched up to April 2024 for published studies, using the keyword "DNA-TG" with MeSH terms and synonyms. The electronic search strategy was augmented by a manual examination of references cited in articles, recent reviews, editorials, and meta-analyses. A meta-analysis was performed using R studio 4.1.3. to investigate the difference between the coefficients (Fisher's z-transformed correlation coefficient) of DNA-TG and 6-TGNs levels. A meta-analysis was performed using RevMan version 5.4 to investigate the difference in DNA-TG levels between patients with or without leukopenia using randomized effect size model. The risk of bias was assessed using the Newcastle-Ottowa quality assessment scale. RESULTS In this systematic review, 21 studies were included that measured DNA-TG levels in white blood cells for either patients with ALL (n = 16) or IBD (n = 5). In our meta-analysis, the overall mean difference between patients with leukopenia (ALL + IBD) versus no leukopenia was 134.15 fmol TG/µg DNA [95% confidence interval (CI) (83.78-184.35), P < 0.00001; heterogeneity chi squared of 5.62, I2 of 47%]. There was a significant difference in DNA-TG levels for patients with IBD with and without leukopenia [161.76 fmol TG/µg DNA; 95% CI (126.23-197.29), P < 0.00001; heterogeneity chi squared of 0.20, I2 of 0%]. No significant difference was found in DNA-TG level between patients with ALL with or without leukopenia (57.71 fmol TG/µg DNA [95% CI (- 22.93 to 138.35), P < 0.80]). DNA-TG monitoring was found to be a promising method for predicting relapse rates in patients with ALL, and DNA-TG levels are likely a better predictor for leukopenia in patients with IBD than RBC 6-TGNs levels. DNA-TG levels have been shown to correlate with various gene variants (TPMT, NUDT15, ITPA, and MRP4) in various studies, points to its potential as a more informative marker for guiding thiopurine therapy across diverse genetic backgrounds. CONCLUSIONS This systematic review strongly supports the further investigation of DNA-TG as a marker for monitoring thiopurine therapy. Its correlation with treatment outcomes, such as relapse-free survival in ALL and the risk of leukopenia in IBD, underscores its role in enhancing personalized treatment approaches. DNA-TG effectively identifies NUDT15 variants and predicts late leukopenia in patients with IBD, regardless of their NUDT15 variant status. The recommended threshold for late leukopenia prediction in patients with IBD with DNA-TG is suggested to be between 320 and 340 fmol/µg DNA. More clinical research on DNA-TG implementation is mandatory to improve patient care and to improve inclusivity in thiopurine treatment.
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Affiliation(s)
- Ahmed B Bayoumy
- Department of Internal Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, The Netherlands.
| | - A R Ansari
- Department of Gastroenterology and Hepatology, London Bridge Hospital, London, UK
| | - C J J Mulder
- Department of Gastroenterology and Hepatology, AGEM Research Institute, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - K Schmiegelow
- Department of Pediatrics and Adolescent Medicine, The Juliane Marie Centre, The University Hospital Rigshospitalet, Copenhagen, Denmark
- Institute of Clinical Medicine, The Faculty of Health Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Timothy Florin
- Mater Research, University of Queensland, Translational Research Institute, Woolloongabba, QLD, 4102, Australia
| | - N K H De Boer
- Department of Gastroenterology and Hepatology, AGEM Research Institute, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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15
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Rosdiana DS, Saputri DS, Louisa M, Setiabudy R. NUDT15 Polymorphism and Its Association With Mercaptopurine Hematotoxicity in Acute Lymphoblastic Leukemia in Indonesian Children. In Vivo 2024; 38:2041-2048. [PMID: 38936894 PMCID: PMC11215610 DOI: 10.21873/invivo.13662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 04/22/2024] [Accepted: 04/25/2024] [Indexed: 06/29/2024]
Abstract
BACKGROUND/AIM Hematotoxicity is a life-threatening condition that has become the major cause of drug discontinuation in patients with acute lymphoblastic leukemia (ALL). The nudix hydrolase 15 (NUDT15) gene polymorphism (c.415C>T) is reported to have an association with the hematotoxicity of 6-mercaptopurine (6-MP) as maintenance therapy in patients with ALL. However, the prevalence of this genetic polymorphism in the Indonesian population is unknown. This study aimed to assess the frequency of NUDT15 polymorphism among Indonesian pediatric patients with ALL and its association with the hematotoxicity of 6-MP. PATIENTS AND METHODS A total of 101 stored DNA samples from pediatric patients with ALL receiving 6-MP treatment were used for genetic testing. Direct sequencing was conducted to determine the NUDT15 c.415C>T genotype. Chi-square or Fisher's exact test were employed to examine the association between the NUDT15 c.415C>T genotype and hematotoxicity. RESULTS All (100%) of the DNA samples from patients with ALL treated with 6-MP exhibited a homozygous variant of the NUDT15 c.415C>T genotype, 70.3% of which showed hematotoxicity to some extent. We found no significant differences in NUDT15 gene polymorphism among patients with ALL with different states of hematotoxicity. CONCLUSION The observed high frequency of NUDT15 c.415C>T in our study population might explain the elevated prevalence of 6-MP-associated hematotoxicity in pediatric patients with ALL within the Indonesian population. Our study provides new insight regarding the NUDT15 gene polymorphism and its relation to hematotoxicity. Further studies are required to determine the necessity of adjusting the initial dose of 6-MP for Indonesian pediatric patients with ALL.
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Affiliation(s)
- Dewi Selvina Rosdiana
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia;
| | - Dianita Susilo Saputri
- Department of Genome Informatics, Research Institute for Microbial Diseases, Osaka University, Suita, Japan
| | - Melva Louisa
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Rianto Setiabudy
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
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16
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Pagliaro L, Chen SJ, Herranz D, Mecucci C, Harrison CJ, Mullighan CG, Zhang M, Chen Z, Boissel N, Winter SS, Roti G. Acute lymphoblastic leukaemia. Nat Rev Dis Primers 2024; 10:41. [PMID: 38871740 DOI: 10.1038/s41572-024-00525-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/01/2024] [Indexed: 06/15/2024]
Abstract
Acute lymphoblastic leukaemia (ALL) is a haematological malignancy characterized by the uncontrolled proliferation of immature lymphoid cells. Over past decades, significant progress has been made in understanding the biology of ALL, resulting in remarkable improvements in its diagnosis, treatment and monitoring. Since the advent of chemotherapy, ALL has been the platform to test for innovative approaches applicable to cancer in general. For example, the advent of omics medicine has led to a deeper understanding of the molecular and genetic features that underpin ALL. Innovations in genomic profiling techniques have identified specific genetic alterations and mutations that drive ALL, inspiring new therapies. Targeted agents, such as tyrosine kinase inhibitors and immunotherapies, have shown promising results in subgroups of patients while minimizing adverse effects. Furthermore, the development of chimeric antigen receptor T cell therapy represents a breakthrough in ALL treatment, resulting in remarkable responses and potential long-term remissions. Advances are not limited to treatment modalities alone. Measurable residual disease monitoring and ex vivo drug response profiling screening have provided earlier detection of disease relapse and identification of exceptional responders, enabling clinicians to adjust treatment strategies for individual patients. Decades of supportive and prophylactic care have improved the management of treatment-related complications, enhancing the quality of life for patients with ALL.
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Affiliation(s)
- Luca Pagliaro
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Translational Hematology and Chemogenomics (THEC), University of Parma, Parma, Italy
- Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Sai-Juan Chen
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Daniel Herranz
- Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Cristina Mecucci
- Department of Medicine, Hematology and Clinical Immunology, University of Perugia, Perugia, Italy
| | - Christine J Harrison
- Leukaemia Research Cytogenetics Group, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Charles G Mullighan
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Ming Zhang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Zhu Chen
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Nicolas Boissel
- Hôpital Saint-Louis, APHP, Institut de Recherche Saint-Louis, Université Paris Cité, Paris, France
| | - Stuart S Winter
- Children's Minnesota Cancer and Blood Disorders Program, Minneapolis, MN, USA
| | - Giovanni Roti
- Department of Medicine and Surgery, University of Parma, Parma, Italy.
- Translational Hematology and Chemogenomics (THEC), University of Parma, Parma, Italy.
- Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
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17
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Maillard M, Nishii R, Yang W, Hoshitsuki K, Chepyala D, Lee SHR, Nguyen JQ, Relling MV, Crews KR, Leggas M, Singh M, Suang JLY, Yeoh AEJ, Jeha S, Inaba H, Pui CH, Karol SE, Trehan A, Bhatia P, Antillon Klussmann FG, Bhojwani D, Haidar CE, Yang JJ. Additive effects of TPMT and NUDT15 on thiopurine toxicity in children with acute lymphoblastic leukemia across multiethnic populations. J Natl Cancer Inst 2024; 116:702-710. [PMID: 38230823 PMCID: PMC11077315 DOI: 10.1093/jnci/djae004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 12/22/2023] [Accepted: 01/04/2024] [Indexed: 01/18/2024] Open
Abstract
BACKGROUND Thiopurines such as mercaptopurine (MP) are widely used to treat acute lymphoblastic leukemia (ALL). Thiopurine-S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) inactivate thiopurines, and no-function variants are associated with drug-induced myelosuppression. Dose adjustment of MP is strongly recommended in patients with intermediate or complete loss of activity of TPMT and NUDT15. However, the extent of dosage reduction recommended for patients with intermediate activity in both enzymes is currently not clear. METHODS MP dosages during maintenance were collected from 1768 patients with ALL in Singapore, Guatemala, India, and North America. Patients were genotyped for TPMT and NUDT15, and actionable variants defined by the Clinical Pharmacogenetics Implementation Consortium were used to classify patients as TPMT and NUDT15 normal metabolizers (TPMT/NUDT15 NM), TPMT or NUDT15 intermediate metabolizers (TPMT IM or NUDT15 IM), or TPMT and NUDT15 compound intermediate metabolizers (TPMT/NUDT15 IM/IM). In parallel, we evaluated MP toxicity, metabolism, and dose adjustment using a Tpmt/Nudt15 combined heterozygous mouse model (Tpmt+/-/Nudt15+/-). RESULTS Twenty-two patients (1.2%) were TPMT/NUDT15 IM/IM in the cohort, with the majority self-reported as Hispanics (68.2%, 15/22). TPMT/NUDT15 IM/IM patients tolerated a median daily MP dose of 25.7 mg/m2 (interquartile range = 19.0-31.1 mg/m2), significantly lower than TPMT IM and NUDT15 IM dosage (P < .001). Similarly, Tpmt+/-/Nudt15+/- mice displayed excessive hematopoietic toxicity and accumulated more metabolite (DNA-TG) than wild-type or single heterozygous mice, which was effectively mitigated by a genotype-guided dose titration of MP. CONCLUSION We recommend more substantial dose reductions to individualize MP therapy and mitigate toxicity in TPMT/NUDT15 IM/IM patients.
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Affiliation(s)
- Maud Maillard
- Department of Pharmacy and Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN, USA
| | - Rina Nishii
- Department of Pharmacy and Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN, USA
| | - Wenjian Yang
- Department of Pharmacy and Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN, USA
| | - Keito Hoshitsuki
- Department of Pharmacy and Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN, USA
| | - Divyabharathi Chepyala
- Department of Pharmacy and Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN, USA
| | - Shawn H R Lee
- Department of Pharmacy and Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN, USA
- Khoo Teck Puat-National University Children’s Medical Institute, National University Hospital, National University Health System, Singapore, Singapore
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jenny Q Nguyen
- Personalized Care Program, Children’s Hospital Los Angeles, Los Angeles, CA, USA
| | - Mary V Relling
- Department of Pharmacy and Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN, USA
| | - Kristine R Crews
- Department of Pharmacy and Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN, USA
| | - Mark Leggas
- Department of Pharmacy and Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN, USA
| | - Meenu Singh
- Haematology-Oncology Unit, Department of Paediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Joshua L Y Suang
- Khoo Teck Puat-National University Children’s Medical Institute, National University Hospital, National University Health System, Singapore, Singapore
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Allen E J Yeoh
- Khoo Teck Puat-National University Children’s Medical Institute, National University Hospital, National University Health System, Singapore, Singapore
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Sima Jeha
- Department of Oncology, St Jude Children’s Research Hospital, Memphis, TN, USA
- Department of Global Pediatric Medicine, St Jude Children’s Research Hospital, Memphis, TN, USA
| | - Hiroto Inaba
- Department of Oncology, St Jude Children’s Research Hospital, Memphis, TN, USA
| | - Ching-Hon Pui
- Department of Oncology, St Jude Children’s Research Hospital, Memphis, TN, USA
- Department of Global Pediatric Medicine, St Jude Children’s Research Hospital, Memphis, TN, USA
| | - Seth E Karol
- Department of Oncology, St Jude Children’s Research Hospital, Memphis, TN, USA
| | - Amita Trehan
- Haematology-Oncology Unit, Department of Paediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Prateek Bhatia
- Haematology-Oncology Unit, Department of Paediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | | | - Deepa Bhojwani
- Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Cyrine E Haidar
- Department of Pharmacy and Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN, USA
| | - Jun J Yang
- Department of Pharmacy and Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN, USA
- Department of Oncology, St Jude Children’s Research Hospital, Memphis, TN, USA
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Massey JC, Magagnoli J, Sutton SS, Buckhaults PJ, Wyatt MD. Collateral damage of NUDT15 deficiency in cancer provides a cancer pharmacogenetic therapeutic window with thiopurines. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.08.588560. [PMID: 38645136 PMCID: PMC11030356 DOI: 10.1101/2024.04.08.588560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/23/2024]
Abstract
Genome instability is a hallmark of cancer and are driven by mutations in oncogenes and tumor suppressor genes. Despite successes seen with select targeted therapeutics, this type of personalized medicine is only beneficial for a small subpopulation of cancer patients who have one of a few actionable genetic changes. Most tumors also contain hundreds of passenger mutations that offered no fitness advantage or disadvantage during tumor evolution. Mutations in known pharmacogenetic (PGx) loci for which germline variants encode variability in drug response can cause somatically acquired drug sensitivity. The NUDT15 gene is a known PGx locus that participates in the rate-limiting metabolism of thiopurines. People with two defective germline alleles of NUDT15 are hypersensitive to the toxic effects of thiopurines. NUDT15 is located adjacent to the Retinoblastoma ( RB1 ) tumor suppressor gene, which often undergoes homozygous deletion in retinoblastomas and other epithelial cancers. We observed that RB1 undergoes homozygous deletions in 9.4% of prostate adenocarcinomas and 2.5% of ovarian cancers, and in nearly all of these cases NUDT15 is also lost. Moreover, 44% of prostate adenocarcinomas and over 60% of ovarian cancers have lost one allele of NUDT15, which predicts that a majority of all prostate and ovarian cancers have somatically acquired hypersensitivity to thiopurine treatment. We performed a retrospective analysis of >16,000 patients in the US Veterans Administration health care system and found concurrent xanthine oxidase inhibition (XOi) and thiopurine usage for non-cancer indications is significantly associated with reduced incidence of prostate cancer. The hazard ratio for the development of prostate cancer in patients treated with thiopurines and XOi was 0.562 (0.301-1.051) for the unmatched cohort and 0.389 (0.185-0.819) for the propensity score matched cohort. We experimentally depleted NUDT15 from ovarian and prostate cancer cell lines and observed a dramatic sensitization to thiopurine-induced and DNA damage-dependent toxicity. These results indicate that somatic loss of NUDT15 predicts therapeutic sensitivity to a low cost and well tolerated drug with a broad therapeutic window.
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Shriver SP, Adams D, McKelvey BA, McCune JS, Miles D, Pratt VM, Ashcraft K, McLeod HL, Williams H, Fleury ME. Overcoming Barriers to Discovery and Implementation of Equitable Pharmacogenomic Testing in Oncology. J Clin Oncol 2024; 42:1181-1192. [PMID: 38386947 PMCID: PMC11003514 DOI: 10.1200/jco.23.01748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 11/08/2023] [Accepted: 12/12/2023] [Indexed: 02/24/2024] Open
Abstract
Pharmacogenomics (PGx), the study of inherited genomic variation and drug response or safety, is a vital tool in precision medicine. In oncology, testing to identify PGx variants offers patients the opportunity for customized treatments that can minimize adverse effects and maximize the therapeutic benefits of drugs used for cancer treatment and supportive care. Because individuals of shared ancestry share specific genetic variants, PGx factors may contribute to outcome disparities across racial and ethnic categories when genetic ancestry is not taken into account or mischaracterized in PGx research, discovery, and application. Here, we examine how the current scientific understanding of the role of PGx in differential oncology safety and outcomes may be biased toward a greater understanding and more complete clinical implementation of PGx for individuals of European descent compared with other genetic ancestry groups. We discuss the implications of this bias for PGx discovery, access to care, drug labeling, and patient and provider understanding and use of PGx approaches. Testing for somatic genetic variants is now the standard of care in treatment of many solid tumors, but the integration of PGx into oncology care is still lacking despite demonstrated actionable findings from PGx testing, reduction in avoidable toxicity and death, and return on investment from testing. As the field of oncology is poised to expand and integrate germline genetic variant testing, it is vital that PGx discovery and application are equitable for all populations. Recommendations are introduced to address barriers to facilitate effective and equitable PGx application in cancer care.
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Affiliation(s)
| | | | | | - Jeannine S McCune
- City of Hope/Beckman Research Institute Department of Hematologic Malignancies Translational Sciences, Duarte, CA
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20
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Du S, Huang X, He X, Mao M, Chen M, Zhang R, Shao H, Lv Z, Liu X, Chuan J. Association of NUDT15 gene polymorphism with adverse reaction, treatment efficacy, and dose of 6-mercaptopurine in patients with acute lymphoblastic leukemia: a systematic review and meta-analysis. Haematologica 2024; 109:1053-1068. [PMID: 37794799 PMCID: PMC10985454 DOI: 10.3324/haematol.2023.282761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 10/26/2023] [Indexed: 10/06/2023] Open
Abstract
6-mercaptopurine (6-MP) serves as the backbone in the maintenance regimens of acute lymphoblastic leukemia (ALL). We aimed to evaluate the influence of NUDT15 gene polymorphism on the risk of myelosupression, hepatotoxicity and interruption of 6-MP, as well as treatment efficacy and dose of 6-MP in ALL patients. A total of 24 studies with 3,374 patients were included in this meta-analysis. We found 9-fold higher risk of 6-MP induced leukopenia (odds ratio [OR] =9.00, 95% confidence interval [CI]: 3.73-21.74) and 2.5-fold higher risk of 6-MP-induced neutropenia (OR=2.52, 95% CI: 1.72-3.69) for NUDT15 c.415C>T variant carriers in the dominant model. Moreover, we found that the dose intensity of 6-MP in ALL patients with one NUDT15 c.415C>T variant alleles (CT) was 19% less than that in wild-type patients (CC) (mean differences: 19.43%, 95% CI: -25.36 to -13.51). The tolerable dose intensity of 6-MP in NUDT15 c.415C>T homozygote variant (TT) and heterozygote variant (CT) carriers was 49% and 15% less than that in wild-type patients, respectively. The NUDT15 c.415C>T variant group (CT+TT) had seven times (OR=6.98, 95% CI: 2.83-17.22) higher risk of developing 6-MP intolerance than the CC group. However, NUDT15 c.415C>T polymorphism did not appear significantly associated with hepatotoxicity, treatment interruption or relapse incidence. We concluded that NUDT15 c.415C>T was a good predictor for 6-MP-induced myelosuppression in ALL patients. The dose intensity of 6-MP in ALL patients with NUDT15 c.415C>T variants was significantly lower than that in wild-type patients. This research provided a basis for further investigation into relations between NUDT15 gene and adverse reaction, treatment efficacy and dose intensity of 6-MP.
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Affiliation(s)
- Shan Du
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu
| | - Xuefei Huang
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu
| | - Xia He
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu
| | - Mian Mao
- Department of Pharmacy, Sichuan Cancer Hospital, Chengdu
| | - Min Chen
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu
| | - Rong Zhang
- Department of Pediatrics, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu
| | - Huikai Shao
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu
| | - Ziyan Lv
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu
| | - Xinxia Liu
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu.
| | - Junlan Chuan
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu.
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21
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Muhammad M, Saifo M, Aljamali M, Alali M, Ghanem KM. The frequency of NUDT15 rs116855232 and its impact on mercaptopurine-induced toxicity in Syrian children with acute lymphoblastic leukemia. Front Oncol 2024; 14:1334846. [PMID: 38562167 PMCID: PMC10982510 DOI: 10.3389/fonc.2024.1334846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 02/27/2024] [Indexed: 04/04/2024] Open
Abstract
Introduction Polymorphisms in NUDT15 may result in differences in mercaptopurine-induced toxicity. This study aimed to identify the frequency of the NUDT15 (c.415C>T; rs116855232) polymorphism and investigate the effect of this polymorphism on mercaptopurine-induced toxicity in a population of Syrian patients with childhood acute lymphoblastic leukemia (ALL). Methods This is a retrospective study that included children with ALL reaching at least 6 months of maintenance therapy. The NUDT15 genotyping was determined using standard targeted sequencing of polymerase chain reaction products. The odds ratio (OR) for the association between toxicity and genotype was evaluated. Results A total of 92 patients were enrolled. The majority of the patients in the study population were low-risk (63.04%), followed by intermediate-risk (25%), and high-risk (11.96%). There were 5 patients (5.4%) with NUDT15 (c.415C>T; rs116855232) CT genotype, and 1 patient (1.08%) with NUDT15 TT genotype, with allele frequencies of C=0.962 and T=0.038. The mercaptopurine median dose intensity was 100%, 54.69%, and 5% for the genotypes CC, CT, and TT, respectively (P=0.009). Early onset leukopenia was significantly associated with the NUDT15 polymorphism (OR: 6.16, 95% CI: 1.11-34.18, P=0.037). There was no association between the NUDT15 genotype and hepatotoxicity. Conclusion Approximately 6.5% of the study population exhibited reduced NUDT15 activity. The mercaptopurine dose intensity was considerably low in NUDT15 rs116855232 TT genotype compared with CT and CC. The dosage of mercaptopurine should be adjusted according to the NUDT15 genotype in pediatric patients with ALL.
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Affiliation(s)
- Muhammad Muhammad
- BASMA Pediatric Oncology Unit, Damascus, Syria
- Department of Oncology, Albairouni University Hospital, Faculty of Medicine, Damascus University, Damascus, Syria
| | - Maher Saifo
- Department of Oncology, Albairouni University Hospital, Faculty of Medicine, Damascus University, Damascus, Syria
- Faculty of Medicine, Damascus University, Damascus, Syria
| | - Majd Aljamali
- Department of Biochemistry and Microbiology, Faculty of Pharmacy, Damascus University, Damascus, Syria
- National Commission for Biotechnology (NCBT), Damascus, Syria
| | - Mousa Alali
- Department of Oncology, Albairouni University Hospital, Faculty of Medicine, Damascus University, Damascus, Syria
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22
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Okamoto H, Tanaka Y, Shibagaki Y, Kuronuma S, Miyatani Y, Umeda S, Mishiro-Sato E, Takeuchi O, Hattori S, Kobayashi T, Okuwaki M. Measurement of the intracellular active metabolites of thiopurine drugs to evaluate the enzymatic activity of nudix hydrolase 15 in human blood samples. J Chromatogr B Analyt Technol Biomed Life Sci 2024; 1234:123993. [PMID: 38246006 DOI: 10.1016/j.jchromb.2024.123993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 12/13/2023] [Accepted: 01/01/2024] [Indexed: 01/23/2024]
Abstract
Thiopurine is metabolized to 6-thio-(deoxy) guanosine triphosphate (6-thio-(d) GTP), which is then incorporated into DNA or RNA and causes cytotoxicity. Nudix hydrolase 15 (NUDT15) reduces the cytotoxic effects of thiopurine by converting 6-thio-(d) GTP to 6-thio-(d) guanosine monophosphate (6-thio-(d) GMP). NUDT15 polymorphisms like the Arg139Cys variant are strongly linked to thiopurine-induced severe leukocytopenia and alopecia. Therefore, measurement of NUDT15 enzymatic activity in individual patients can help predict thiopurine tolerability and adjust the dosage. We aimed to develop a quantitative assay for NUDT15 enzymatic activity in human blood samples. Blood samples were collected from donors whose NUDT15 genetic status was determined. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to assess the 6-thio-GTP metabolic activity in cell extracts. Because 6-thio-guanosine diphosphate (6-thio-GDP) and 6-thio-GMP were generated upon incubation of 6-thio-GTP with human blood cell extracts, the method detecting 6-thio-GTP, 6-thio-GDP, and 6-thio-GMP was validated. All three metabolites were linearly detected, and the lower limit of quantification (LLOQ) of 6-thio-GTP, 6-thio-GDP, and 6-thio-GMP were 5 μM, 1 μM, and 2 μM, respectively. Matrix effects of human blood cell extracts to detect 6-thio-GTP, 6-thio-GDP, and 6-thio-GMP were 99.0 %, 100.5 %, and 101.4 %, respectively, relative to the signals in the absence of blood cell extracts. The accuracy and precision of the method and the stability of the samples were also assessed. Using this established method, the genotype-dependent differences in NUDT15 activities were successfully determined using cell extracts derived from human blood cells with NUDT15 wild-type (WT) or Arg139Cys variant and 6-thio-GTP (100 μM) as a substrate (18.1, 14.9, and 6.43 μM/h/106 cells for WT, Arg139Cys heterozygous, and homozygous variant, respectively). We developed a method for quantifying intracellular NUDT15 activity in peripheral blood mononuclear cells (PBMCs), which we defined as the conversion of 6-thio-GTP to 6-thio-GMP. Although PBMCs preparation takes some time, its reproducibility in experiments makes it a promising candidate for clinical application. This method can tell the difference between WT and Arg139Cys homozygous blood samples. Even in patients with WT NUDT15, WT samples showed variations in NUDT15 activity, which may correlate with variations in thiopurine dosage.
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Affiliation(s)
- Hitomi Okamoto
- Laboratory of Biochemistry, Graduate School of Pharmaceutical Sciences, Japan; Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan
| | - Yoichi Tanaka
- Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan; Division of Medicinal Safety Science, National Institute of Health Sciences, Kanagawa, Japan.
| | - Yoshio Shibagaki
- Laboratory of Biochemistry, Graduate School of Pharmaceutical Sciences, Japan
| | - Satoshi Kuronuma
- Biomedical Laboratory, Department of Research, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - Yusuke Miyatani
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan; Department of Gastroenterology and Hepatology, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - Satoko Umeda
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan; Department of Gastroenterology and Hepatology, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - Emi Mishiro-Sato
- Laboratory of Biochemistry, Graduate School of Pharmaceutical Sciences, Japan
| | - Osamu Takeuchi
- Biomedical Laboratory, Department of Research, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - Seisuke Hattori
- Laboratory of Biochemistry, Graduate School of Pharmaceutical Sciences, Japan
| | - Taku Kobayashi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan; Department of Gastroenterology and Hepatology, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - Mitsuru Okuwaki
- Laboratory of Biochemistry, Graduate School of Pharmaceutical Sciences, Japan.
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23
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Moore JN, Campagne O, Bhojwani D, Crowe D, Stewart CF. Developing Therapy for Every Kid With Cancer - Summary of a Scientific Session at the 2023 ASCPT Meeting. Clin Pharmacol Ther 2024; 115:185-187. [PMID: 37997700 DOI: 10.1002/cpt.3101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 11/01/2023] [Indexed: 11/25/2023]
Affiliation(s)
- Jason N Moore
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Olivia Campagne
- Quantitative Clinical Pharmacology, Takeda Development Center Americas, Inc., Cambridge, Massachusetts, USA
| | - Deepa Bhojwani
- Division of Pediatric Hematology Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center and Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Dean Crowe
- Rally Foundation for Childhood Cancer Research, Atlanta, Georgia, USA
| | - Clinton F Stewart
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
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24
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Zhou Y, Wang L, Sun LR, Zhang L, Wang HM, Liu XT, Yang F, Wu KL, Liang YL, Zhao BB, Zhuang Y, Fu JQ, Song C, Li Y, Wang LZ, Xu HJ, Gu Y, van den Anker J, Ju XL, Zhu XF, Zhao W. Individualized Use of 6-Mercaptopurine in Chinese Children with ALL: A Multicenter Randomized Controlled Trial. Clin Pharmacol Ther 2024; 115:213-220. [PMID: 37753808 DOI: 10.1002/cpt.3061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 09/19/2023] [Indexed: 09/28/2023]
Abstract
Continuous 6-mercaptopurine (6-MP) dose titration is necessary because of its narrow therapeutic index and frequently encountered dose-limiting hematopoietic toxicity. However, evidence-based guidelines for gene-based 6-MP dosing have not been established for Chinese children with acute lymphoblastic leukemia (ALL). This multicenter, randomized, open-label, active-controlled clinical trial randomly assigned Chinese children with low- or intermediate-risk ALL in a 1:1 ratio to receive TPMT-NUDT15 gene-based dosing of 6-MP (N = 44, 10 to 50 mg/m2 /day) or standard dosing (N = 44, 50 mg/m2 /day) during maintenance therapy. The primary end point was the incidence of 6-MP myelosuppression in both groups. Secondary end points included frequencies of 6-MP hepatotoxicity, duration of myelosuppression and leukopenia, event-free survival, and steady-state concentrations of active metabolites (6-thioguaninenucleotides and 6-methylmercaptopurine nucleotides) in erythrocytes. A 2.2-fold decrease in myelosuppression, the primary end point, was observed in the gene-based-dose group using ~ 50% of the standard initial 6-MP dose (odds ratio, 0.26, 95% confidence interval, 0.11 to 0.64, P = 0.003). Patients in the gene-based-dose group had a significantly lower risk of developing thiopurine-induced myelosuppression and leukopenia (P = 0.015 and P = 0.022, respectively). No significant differences were observed in the secondary end points of the incidence of hepatotoxicity and steady-state concentrations of active metabolites in erythrocytes between the two groups. TPMT- and NUDT15-based dosing of 6-MP will significantly contribute toward further reducing the incidence of leukopenia in Chinese children with ALL. This trial is registered at www.clinicaltrial.gov as #NCT04228393.
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Affiliation(s)
- Yue Zhou
- Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Li Wang
- Department of Pediatric Hematology Oncology, Children's Hospital of Hebei Province affiliated to Hebei Medical University, Shijiazhuang, China
| | - Li-Rong Sun
- Department of Pediatrics Hematology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Li Zhang
- Department of Pediatrics, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Hong-Mei Wang
- Department of Pediatrics, The First Affiliated Hospital of Shandong, First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Xi-Ting Liu
- Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Pharmacy, China-Japan Friendship Hospital, Beijing, China
| | - Fan Yang
- Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ke-Liang Wu
- Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yu-Li Liang
- Department of Pediatric Hematology Oncology, Children's Hospital of Hebei Province affiliated to Hebei Medical University, Shijiazhuang, China
| | - Bei-Bei Zhao
- Department of Pediatrics, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Yong Zhuang
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China
| | - Jin-Qiu Fu
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China
| | - Chao Song
- The State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, China
| | - Yun Li
- The State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, China
| | - Ling-Zhen Wang
- Department of Pediatrics Hematology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hui-Juan Xu
- Department of Pediatrics Hematology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yan Gu
- Department of Pediatrics, The First Affiliated Hospital of Shandong, First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - John van den Anker
- Division of Clinical Pharmacology, Children's National Medical Center, Washington, DC, USA
- Departments of Pediatrics, Pharmacology & Physiology, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA
- Department of Paediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel, Basel, Switzerland
| | - Xiu-Li Ju
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China
| | - Xiao-Fan Zhu
- Department of Pediatrics, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Wei Zhao
- Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
- NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Shandong University, Jinan, China
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25
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Yokota Y, Imai T, Kawahara M, Inatomi O, Nishida A, Kakuta Y, Masamune A, Andoh A. Thiopurines exert harmful effects on spermatogenesis in Nudt15 R138C knock-in mice. J Gastroenterol 2024; 59:109-118. [PMID: 38097780 DOI: 10.1007/s00535-023-02059-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 11/07/2023] [Indexed: 01/26/2024]
Abstract
BACKGROUND The association between thiopurine use and testicular reproductive functions remains unclear. In this study, we investigated whether thiopurines affect testicular functions based on the NUDT15 genotypes using Nudt15R138C knock-in mice. METHODS The male Nudt15R138C knock-in mice (9-12 weeks) were treated with mercaptopurine (MP: 0.5 mg/kg/day) for 4 or 12 weeks. To examine reversibility, some mice were maintained for a further 12 weeks under MP-free condition. RESULTS After MP treatment for 4 weeks, Nudt15R138C/R138C mice exhibited a significant reduction of testis weight compared to Nudt15+/+ mice and Nudt15+/R138C mice. The epithelial height and diameter of seminiferous tubules were significantly reduced in Nudt15R138C/R138C mice compared to Nudt15+/+ and Nudt15+/R138C mice. Apoptotic cells were significantly increased in Nudt15R138C/R138C mice, and most of apoptotic cells were spermatogonia. There were no significant changes in sperm counts and sperm morphology in MP-treated Nudt15R138C/R138C mice after 4-week MP treatment. On the other hand, after MP treatment for 12 weeks, the Nudt15+/R138C mice, but not Nudt15+/+ mice, exhibited a significant reduction in the testis weight and atrophic changes of seminiferous tubules, but these changes disappeared after 12-week rearing under MP-free condition. Despite a significant increase in abnormal sperm rate, there were no changes in the ability to conceive. No differences in serum levels of follicle-stimulating hormone or testosterone were observed between MP-treated Nudt15+/R138C and Nudt15+/+ mice after 12-week MP treatment. CONCLUSIONS Thiopurines exert harmful effects on testicular reproductive function according to host NUDT15 genotypes.
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Affiliation(s)
- Yoshihiro Yokota
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Takayuki Imai
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Masahiro Kawahara
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Osamu Inatomi
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Atsushi Nishida
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Yoichi Kakuta
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8575, Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8575, Japan
| | - Akira Andoh
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan.
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Zhao L, Giacomini KM, van der Graaf PH. Progress in Clinical Pharmacology in China: A Randomized Controlled Study to Advance Genotype-Guided Precision Medicine. Clin Pharmacol Ther 2024; 115:169-172. [PMID: 38252417 DOI: 10.1002/cpt.3126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 12/04/2023] [Indexed: 01/23/2024]
Affiliation(s)
- Liang Zhao
- Division of Quantitative Methods in Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Kathleen M Giacomini
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA
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Díaz-Villamarín X, Fernández-Varón E, Rojas Romero MC, Callejas-Rubio JL, Cabeza-Barrera J, Rodríguez-Nogales A, Gálvez J, Morón R. Azathioprine dose tailoring based on pharmacogenetic information: Insights of clinical implementation. Biomed Pharmacother 2023; 168:115706. [PMID: 37857254 DOI: 10.1016/j.biopha.2023.115706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 10/05/2023] [Accepted: 10/11/2023] [Indexed: 10/21/2023] Open
Abstract
Azathioprine is commonly used as an immunosuppressive antimetabolite in the treatment of acute lymphoblastic leukemia, autoimmune disorders (such as Crohn's disease and rheumatoid arthritis), and in patients receiving organ transplants. Thiopurine-S-methyltransferase (TPMT) is a cytoplasmic trans-methylase catalyzing the S-methylation of thiopurines. The active metabolites obtained from thiopurines are hydrolyzed into inactive forms by the Nudix hydrolase 15 (NUDT15). The TPMT*2 (defined by rs1800462), *3A (defined by rs1800460 and rs1142345), *3B (defined by rs1800460), *3C (defined by rs1142345), *6 (defined by rs75543815), and NUDT15 rs116855232 genetic variant have been associated, with the highest level of evidence, with the response to azathioprine, and, the approved drug label for azathioprine and main pharmacogenetic dosing guidelines recommend starting with reduced initial doses in TPMT intermediate metabolizer (IM) patients and considering an alternative treatment in TPMT poor metabolizer (PM) patients. This study aims to assess the clinical impact of azathioprine dose tailoring based on TPMT genotyping studying the azathioprine toxicity and efficacy, treatment starts, and dose adjustments during follow-up, comparing TPMT IM/PM and normal metabolizer (NM) patients. It also studied the association of NUDT15 rs116855232 with response to azathioprine in patients receiving a tailored treatment based on TPMT and characterized the TMPT and NUDT15 studied variants in our population. Results show that azathioprine dose reduction in TPMT IM patients (TPMT*1/*2, *1/*3A, or *1/*3C genotypes) is related to lower toxicity events compared to TPMT NM (TPMT *1/*1 genotype), and lower azathioprine dose adjustments during follow-up without showing differences in the efficacy. The results support the hypothesis of existing other genetic variants affecting azathioprine toxicity.
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Affiliation(s)
| | - Emilio Fernández-Varón
- Instituto de Investigación Biosanitaria de Granada (Ibs.Granada), Granada, Spain; Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
| | | | - José Luis Callejas-Rubio
- Instituto de Investigación Biosanitaria de Granada (Ibs.Granada), Granada, Spain; Internal Medicine Department, Hospital Universitario San Cecilio, Granada, Spain
| | - José Cabeza-Barrera
- Instituto de Investigación Biosanitaria de Granada (Ibs.Granada), Granada, Spain; Hospital Pharmacy Unit. Hospital Universitario San Cecilio, Granada, Spain
| | - Alba Rodríguez-Nogales
- Instituto de Investigación Biosanitaria de Granada (Ibs.Granada), Granada, Spain; Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
| | - Julio Gálvez
- Instituto de Investigación Biosanitaria de Granada (Ibs.Granada), Granada, Spain; Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain; Centro de Investigaciones Biomédicas en Red - Enfermedades Hepáticas y Digestivas (CIBER-ehd)
| | - Rocío Morón
- Instituto de Investigación Biosanitaria de Granada (Ibs.Granada), Granada, Spain; Hospital Pharmacy Unit. Hospital Universitario San Cecilio, Granada, Spain
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Tram DB, Chuong HQ, Phuong HA, Phung NTN, Nguyen ML, Vu HA. A Simple, Rapid, and Cost-Effective PCR Procedure for Detection of NUDT15 Gene Variants in Vietnamese Patients with Acute Lymphoblastic Leukemia. J Lab Physicians 2023; 15:567-572. [PMID: 37780869 PMCID: PMC10539051 DOI: 10.1055/s-0043-1768948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 04/05/2023] [Indexed: 10/03/2023] Open
Abstract
Objective The NUDT15 variants impact thiopurine dose selection in acute lymphoblastic leukemia patients. The ability to rapidly detect variants is important in clinical practice. This study aims to develop a simple polymerase chain reaction (PCR) procedure for detecting NUDT15 variants in Vietnamese patients. Materials and Methods Sanger sequencing was used to determine NUDT15 variants from 200 patients. We designed primers and optimized the PCR procedure for detection of wild-type and variant alleles and compared with Sanger sequencing results. Results The inserted variant c.55_56insGAGTCG was detected by differences in size through conventional PCR. The tetra-primer amplification refractory mutation system PCR was successful in detecting two variations, c.52G > A and c.415C > T. The sensitivity and specificity of PCR procedure achieved 100% when compared to 200 Sanger sequencing results. Conclusion Our PCR procedure is suitable for replacing Sanger sequencing to detect the NUDT15 variants in clinical setting.
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Affiliation(s)
- Duong Bich Tram
- Center for Molecular Biomedicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Ho Quoc Chuong
- Center for Molecular Biomedicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Huynh Anh Phuong
- Center for Molecular Biomedicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Nguyen The Nguyen Phung
- Pediatric Department, Faculty of Medicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Mai-Lan Nguyen
- Pediatric Department, Faculty of Medicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Hoang Anh Vu
- Center for Molecular Biomedicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
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Gallardo-Cóndor J, Naranjo P, Atarihuana S, Coello D, Guevara-Ramírez P, Flores-Espinoza R, Burgos G, López-Cortés A, Cabrera-Andrade A. Population-Specific Distribution of TPMT Deficiency Variants and Ancestry Proportions in Ecuadorian Ethnic Groups: Towards Personalized Medicine. Ther Clin Risk Manag 2023; 19:1005-1018. [PMID: 38050617 PMCID: PMC10693761 DOI: 10.2147/tcrm.s432856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 11/06/2023] [Indexed: 12/06/2023] Open
Abstract
Purpose Thiopurine S-methyltransferase (TPMT) is an enzyme that metabolizes purine analogs, agents used in the treatment of acute lymphoblastic leukemia. Improper drug metabolism leads to toxicity in chemotherapy patients and reduces treatment effectiveness. TPMT variants associated with reduced enzymatic activity vary across populations. Therefore, studying these variants in heterogeneous populations, such as Ecuadorians, can help identify molecular causes of deficiency for this enzyme. Methods We sequenced the entire TPMT coding region in 550 Ecuadorian individuals from Afro-Ecuadorian, Indigenous, Mestizo, and Montubio ethnicities. Moreover, we conducted an ancestry analysis using 46 informative ancestry markers. Results We identified 8 single nucleotide variants in the coding region of TPMT. The most prevalent alleles were TPMT*3A, TPMT*3B, and TPMT*3C, with frequencies of 0.055, 0.012, and 0.015, respectively. Additionally, we found rare alleles TPMT*4 and TPMT*8 with frequencies of 0.005 and 0.003. Correlating the ancestry proportions with TPMT-deficient genotypes, we observed that the Native American ancestry proportion influenced the distribution of the TPMT*1/TPMT*3A genotype (OR = 5.977, p = 0.002), while the contribution of African ancestral populations was associated with the TPMT*1/TPMT*3C genotype (OR = 9.769, p = 0.003). The rates of TPMT-deficient genotypes observed in Mestizo (f = 0.121) and Indigenous (f = 0.273) groups provide evidence for the influence of Native American ancestry and the prevalence of the TPMT*3A allele. In contrast, although Afro-Ecuadorian groups demonstrate similar deficiency rates (f = 0.160), the genetic factors involved are associated with contributions from African ancestral populations, specifically the prevalent TPMT*3C allele. Conclusion The distribution of TPMT-deficient variants offers valuable insights into the populations under study, underscoring the necessity for genetic screening strategies to prevent thiopurine toxicity events among Latin American minority groups.
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Affiliation(s)
| | - Pablo Naranjo
- Facultad de Ingeniería y Ciencias Aplicadas, Universidad de Las Américas, Quito, Ecuador
| | - Sebastián Atarihuana
- Facultad de Ingeniería y Ciencias Aplicadas, Universidad de Las Américas, Quito, Ecuador
| | - Dayana Coello
- Laboratorios de Investigación, Universidad de Las Américas, Quito, Ecuador
| | - Patricia Guevara-Ramírez
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Rodrigo Flores-Espinoza
- Laboratório de Diagnóstico por DNA (LDD), Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Germán Burgos
- One Health Research Group, Facultad de Medicina, Universidad de Las Américas, Quito, Ecuador
- Grupo de Medicina Xenomica, Instituto de Ciencias Forenses, Universidad de Santiago de Compostela, Satiago de Compostela, Spain
| | - Andrés López-Cortés
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Madrid, Spain
| | - Alejandro Cabrera-Andrade
- Escuela de Enfermería, Facultad de Ciencias de la Salud, Universidad de Las Américas, Quito, Ecuador
- Grupo de Bio-Quimioinformática, Universidad de Las Américas, Quito, Ecuador
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Solitano V, Facciorusso A, McGovern DPB, Nguyen T, Colman RJ, Zou L, Boland BS, Syversen SW, Jørgensen KK, Ma C, Armuzzi A, Wilson A, Jairath V, Singh S. HLA-DQA1∗05 Genotype and Immunogenicity to Tumor Necrosis Factor-α Antagonists: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2023; 21:3019-3029.e5. [PMID: 37061107 DOI: 10.1016/j.cgh.2023.03.044] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 03/14/2023] [Accepted: 03/31/2023] [Indexed: 04/17/2023]
Abstract
BACKGROUND & AIMS Identifying patients at high risk of immunogenicity is important when selecting tumor necrosis factor (TNF)-α antagonists in patients with immune-mediated inflammatory diseases (IMIDs). We evaluated the association HLA-DQA1∗05 genotype and risk of immunogenicity with TNF-α antagonists. METHODS Through a systematic review through July 14, 2022, we identified studies in patients with IMIDs treated with TNF-α antagonists, which reported the risk of immunogenicity and/or secondary loss of response in patients with HLA-DQA1∗05 variants. Primary outcome was risk of immunogenicity. We performed random effects meta-analysis and used GRADE to appraise certainty of evidence. RESULTS On meta-analysis of 13 studies (3756 patients; median follow-up, 12 months; 41% with variants), HLA-DQA1∗05 variants were associated with 75% higher risk of immunogenicity compared with non-carriers (relative risk, 1.75; 95% confidence interval, 1.37-2.25) with considerable heterogeneity (I2 = 62%) (low certainty evidence). Positive and negative predictive values of HLA-DQA1∗05 variants for predicting immunogenicity were 30% and 80%, respectively. Proactive therapeutic drug monitoring, but not concomitant use of IMMs, IMIDs, and TNF-α antagonist-type, modified this association. Patients with HLA-DQA1∗05 variants experienced 2.2-fold higher risk of secondary loss of response (6 cohorts; relative risk, 2.24; 95% confidence interval, 1.67-3.00; I2 = 0%) (moderate certainty evidence). CONCLUSION Variants in HLA-DQA1∗05 are associated with an increased risk in immunogenicity and secondary loss of response in patients with IMIDs treated with TNF-α antagonists. However, the positive and negative predictive value is moderate, and decisions on concomitant use of IMMs to prevent immunogenicity should be individualized based on all factors that influence drug clearance.
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Affiliation(s)
- Virginia Solitano
- Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada; Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | | | - Dermot P B McGovern
- F. Widjaja Inflammatory Bowel Research Institute, Cedars-Sinai Medical System, Los Angeles, California
| | - Tran Nguyen
- Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada
| | - Ruben J Colman
- Division of Paediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Stanford University School of Medicine, Stanford, California
| | - Lily Zou
- Department of Statistics and Actuarial Sciences, University of Waterloo, Waterloo, Ontario, Canada
| | - Brigid S Boland
- Department of Statistics and Actuarial Sciences, University of Waterloo, Waterloo, Ontario, Canada
| | - Silje W Syversen
- Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway
| | | | - Christopher Ma
- Division of Gastroenterology and Hepatology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | - Alessandro Armuzzi
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; IBD Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Aze Wilson
- Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada; Division of Clinical Pharmacology, Department of Medicine, Western University, London, Ontario, Canada; Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
| | - Vipul Jairath
- Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
| | - Siddharth Singh
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, California; Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla, California.
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Lukaszewicz M, Ferenc-Mrozek A, Kokosza J, Stefaniuk A, Stepinski J, Bojarska E, Darzynkiewicz E. Mammalian Nudt15 hydrolytic and binding activity on methylated guanosine mononucleotides. EUROPEAN BIOPHYSICS JOURNAL : EBJ 2023; 52:487-495. [PMID: 37644211 PMCID: PMC10618335 DOI: 10.1007/s00249-023-01678-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 07/06/2023] [Accepted: 08/14/2023] [Indexed: 08/31/2023]
Abstract
The Nudt15 enzyme of the NUDIX protein family is the subject of extensive study due to its action on thiopurine drugs used in the treatment of cancer and inflammatory diseases. In addition to thiopurines, Nudt15 is enzymatically active in vitro on several nucleotide substrates. It has also been suggested that this enzyme may play a role in 5'RNA turnover by hydrolyzing m7GDP, a product of mRNA decapping. However, no detailed studies on this substrate with Nudt15 are available. Here, we analyzed the enzymatic activity of Nudt15 with m7GDP, its triphosphate form m7GTP, and the trimethylated counterparts (m32,2,7GDP and m32,2,7GTP). Kinetic data revealed a moderate activity of Nudt15 toward these methylated mononucleotides compared to the dGTP substrate. However m7GDP and m32,2,7GDP showed a distinct stabilization of Nudt15 upon ligand binding, in the same range as dGTP, and thus these two mononucleotides may be used as leading structures in the design of small molecule binders of Nudt15.
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Affiliation(s)
- Maciej Lukaszewicz
- Department of Biophysics, Faculty of Physics, University of Warsaw, Pasteura 5, 02-093, Warsaw, Poland.
| | - Aleksandra Ferenc-Mrozek
- Department of Biophysics, Faculty of Physics, University of Warsaw, Pasteura 5, 02-093, Warsaw, Poland
| | - Julia Kokosza
- Department of Biophysics, Faculty of Physics, University of Warsaw, Pasteura 5, 02-093, Warsaw, Poland
| | - Anna Stefaniuk
- Department of Biophysics, Faculty of Physics, University of Warsaw, Pasteura 5, 02-093, Warsaw, Poland
| | - Janusz Stepinski
- Department of Biophysics, Faculty of Physics, University of Warsaw, Pasteura 5, 02-093, Warsaw, Poland
| | - Elzbieta Bojarska
- Department of Biophysics, Faculty of Physics, University of Warsaw, Pasteura 5, 02-093, Warsaw, Poland
| | - Edward Darzynkiewicz
- Department of Biophysics, Faculty of Physics, University of Warsaw, Pasteura 5, 02-093, Warsaw, Poland
- Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097, Warsaw, Poland
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Hertz DL, Lustberg MB, Sonis S. Evolution of predictive risk factor analysis for chemotherapy-related toxicity. Support Care Cancer 2023; 31:601. [PMID: 37773300 DOI: 10.1007/s00520-023-08074-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 09/24/2023] [Indexed: 10/01/2023]
Abstract
The causes of variation in toxicity to the same treatment regimen among seemingly similar patients remain largely unknown. There was tremendous optimism that the patient's germline genome would be strongly predictive of treatment-related toxicity and could be used to personalize treatment and improve therapeutic outcomes. However, there has been limited success in discovering robust pharmacogenetic predictors of treatment-related toxicity and even less progress in translating the few validated predictors into clinical practice. It is apparent that identification of toxicity predictors that can be used to predict and prevent treatment-related toxicity will require thinking beyond germline genomics. To that end, we propose an integrated biomarker discovery approach that recognizes that a patient's toxicity risk is determined by the cumulative effects of a broad range of "omic" and non-omic factors. This commentary describes the limited success in discovering and translating clinical and pharmacogenetic toxicity predictors into clinical practice. We illustrate the evolution of cancer toxicity biomarker discovery and translation through studies of taxane-induced peripheral neuropathy, which is one of the most common and debilitating side effects of cancer treatment. We then discuss the opportunities for discovering non-genomic (e.g., metabolomic, lipidomic, transcriptomic, proteomic, microbiomic, medical, behavioral, environmental) and integrated biomarkers that may be more strongly predictive of toxicity risk and the potential challenges with translating integrated biomarkers into clinical practice. This integrated biomarker discovery approach may circumvent some of the major limitations in toxicity biomarker science and move precision oncology treatment forward so that patients receive maximum treatment benefit with minimal toxicity.
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Affiliation(s)
- Daniel L Hertz
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, 428 Church St., Room 3054 College of Pharmacy, Ann Arbor, MI, 48109-1065, USA.
| | | | - Stephen Sonis
- Divisions of Oral Medicine, Brigham and Women's Hospital and the Dana-Farber Cancer Institute, Boston, MA, 02115, USA
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Huyen DT, Bui TQ, Si NT, Nhat PV, Quy PT, Nhung NTA. Theoretical study of the binding mechanism between anticancerous drug mercaptopurine and gold nanoparticles using a cluster model. J Mol Model 2023; 29:307. [PMID: 37682358 DOI: 10.1007/s00894-023-05716-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 08/31/2023] [Indexed: 09/09/2023]
Abstract
CONTEXT Mercaptopurine is an effective anticancer medicine yet known with serious adverse reactions, thus requiring further attempts to enhance its biological targeting. Small gold clusters Aun (n = 2-10) were used as model reactants to simulate the surface of gold nanoparticles. The computed results show that the drug molecules tend to anchor on the gold clusters at the S atom with the associated binding energies varying from -50 to -34 kcal mol-1 (in vacuum) and from -42 to -28 kcal mol-1 (in aqueous solution). Furthermore, the adsorption of the drug onto the gold surface is considered as a reversible process, and the mechanism of drug releasing was found to be triggerable by internal factors, such as a pH change or the concentrated presence of thiol amino acids in cancerous protein structures. METHOD Calculations based on density functional theory (DFT) were performed to probe the nature of interactions between the drug and gold nanoparticles. Structural features, thermodynamic parameters, bonding characteristics, and electronic properties of the resulting complexes were investigated at the PBE//cc-pVTZ/cc-pVDZ-PP level.
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Affiliation(s)
- Duong Thi Huyen
- Department of Chemistry-Biology, Faculty of Basic Science, Tra Vinh University, Tra Vinh, Vietnam
| | - Thanh Q Bui
- Department of Chemistry, University of Sciences, Hue University, Hue, Vietnam
| | | | - Pham Vu Nhat
- Department of Chemistry, College of Natural Sciences, Can Tho University, Can Tho, Vietnam.
| | - Phan Tu Quy
- Department of Natural Sciences & Technology, Tay Nguyen University, Buon Ma Thuot, Vietnam
| | - Nguyen Thi Ai Nhung
- Department of Chemistry, University of Sciences, Hue University, Hue, Vietnam.
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Shannon ML, Muhammad A, James NT, Williams ML, Breeyear J, Edwards T, Mosley JD, Choi L, Kannankeril P, Van Driest S. Variant-based heritability assessment of dexmedetomidine and fentanyl clearance in pediatric patients. Clin Transl Sci 2023; 16:1628-1638. [PMID: 37353859 PMCID: PMC10499425 DOI: 10.1111/cts.13574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 04/12/2023] [Accepted: 06/01/2023] [Indexed: 06/25/2023] Open
Abstract
Despite complex pathways of drug disposition, clinical pharmacogenetic predictors currently rely on only a few high effect variants. Quantification of the polygenic contribution to variability in drug disposition is necessary to prioritize target drugs for pharmacogenomic approaches and guide analytic methods. Dexmedetomidine and fentanyl, often used in postoperative care of pediatric patients, have high rates of inter-individual variability in dosing requirements. Analyzing previously generated population pharmacokinetic parameters, we used Bayesian hierarchical mixed modeling to measure narrow-sense (additive) heritability (h SNP 2 ) of dexmedetomidine and fentanyl clearance in children and identify relative contributions of small, moderate, and large effect-size variants toh SNP 2 . We used genome-wide association studies (GWAS) to identify variants contributing to variation in dexmedetomidine and fentanyl clearance, followed by functional analyses to identify associated pathways. For dexmedetomidine, median clearance was 33.0 L/h (interquartile range [IQR] 23.8-47.9 L/h) andh SNP 2 was estimated to be 0.35 (90% credible interval 0.00-0.90), with 45% ofh SNP 2 attributed to large-, 32% to moderate-, and 23% to small-effect variants. The fentanyl cohort had median clearance of 8.2 L/h (IQR 4.7-16.7 L/h), with estimatedh SNP 2 of 0.30 (90% credible interval 0.00-0.84). Large-effect variants accounted for 30% ofh SNP 2 , whereas moderate- and small-effect variants accounted for 37% and 33%, respectively. As expected, given small sample sizes, no individual variants or pathways were significantly associated with dexmedetomidine or fentanyl clearance by GWAS. We conclude that clearance of both drugs is highly polygenic, motivating the future use of polygenic risk scores to guide appropriate dosing of dexmedetomidine and fentanyl.
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Affiliation(s)
| | - Ayesha Muhammad
- School of MedicineVanderbilt UniversityNashvilleTennesseeUSA
| | - Nathan T. James
- Department of BiostatisticsVanderbilt University Medical CenterNashvilleTennesseeUSA
- Present address:
Berry Consultants, LLCAustinTexasUSA
| | - Michael L. Williams
- Department of BiostatisticsVanderbilt University Medical CenterNashvilleTennesseeUSA
- Present address:
Department of Clinical Pharmacology and Quantitative PharmacologyAstraZenecaGothenburgSweden
| | - Joseph Breeyear
- Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Todd Edwards
- Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Jonathan D. Mosley
- Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
- Department of Biomedical InformaticsVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Leena Choi
- Department of BiostatisticsVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Prince Kannankeril
- Center for Pediatric Precision Medicine, Department of PediatricsVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Sara Van Driest
- Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
- Center for Pediatric Precision Medicine, Department of PediatricsVanderbilt University Medical CenterNashvilleTennesseeUSA
- Present address:
All of Us Research ProgramNational Institutes of HealthWashingtonDCUSA
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Cook KJ, Grusauskas V, Gloe L, Duong BQ, Gresh RC, Kolb EA, Bansal M, Bechtel AS, Nagasubramanian R, Kirwin SM, Blake KV, Seligson ND. Comparison of variants in TPMT and NUDT15 between sequencing and genotyping methods in a multistate pediatric institution. Clin Transl Sci 2023; 16:1352-1358. [PMID: 37415296 PMCID: PMC10432880 DOI: 10.1111/cts.13539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/30/2023] [Accepted: 04/23/2023] [Indexed: 07/08/2023] Open
Abstract
The risk of severe adverse events related to thiopurine therapy can be reduced by personalizing dosing based on TPMT and NUDT15 genetic polymorphisms. However, the optimal genetic testing platform has not yet been established. In this study, we report on the TPMT and NUDT15 genotypes and phenotypes generated from 320 patients from a multicenter pediatric healthcare system using both Sanger sequencing and polymerase chain reaction genotyping (hereafter: genotyping) methods to determine the appropriateness of genotyping in our patient population. Sanger sequencing identified variant TPMT alleles including *3A (8, 3.2% of alleles), *3C (4, 1.6%), and *2 (1, 0.4%), and NUDT15 alleles including *2 (5, 3.6%) and *3 (1, 0.7%). For genotyped patients, variants identified in TPMT included *3A (12, 3.1%), *3C (4, 1%), *2 (2, 0.5%), and *8 (1, 0.25%), whereas NUDT15 included *4 (2, 1.9%) and *2 or *3 (1, 1%). Between Sanger sequencing and genotyping, no significant difference in allele, genotype, or phenotype frequency was identified for either TPMT or NUDT15. All patients who were tested using Sanger sequencing would have been accurately phenotyped for either TPMT (124/124), NUDT15 (69/69), or both genes (68/68) if they were assayed using the genotyping method. Considering 193 total TPMT and NUDT15 Sanger Sequencing tests reviewed, all tests would have resulted in an appropriate clinical recommendation if the test had instead been conducted using the comparison genotyping platforms. These results suggest that, in this study population, genotyping would be sufficient to provide accurate phenotype calls and clinical recommendations.
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Affiliation(s)
- Kelsey J. Cook
- Precision MedicineNemours Children's HealthJacksonvilleFloridaUSA
- Department of Pharmacotherapy and Translational ResearchThe University of Florida College of PharmacyJacksonvilleFloridaUSA
| | - Victoria Grusauskas
- Precision MedicineNemours Children's HealthJacksonvilleFloridaUSA
- Department of Pharmacotherapy and Translational ResearchThe University of Florida College of PharmacyJacksonvilleFloridaUSA
| | - Lucy Gloe
- Precision MedicineNemours Children's HealthJacksonvilleFloridaUSA
- Department of Pharmacotherapy and Translational ResearchThe University of Florida College of PharmacyJacksonvilleFloridaUSA
| | | | - Renee C. Gresh
- Department of Pediatric Hematology/OncologyNemours Children's HealthWilmingtonDelawareUSA
| | - E. Anders Kolb
- Department of Pediatric Hematology/OncologyNemours Children's HealthWilmingtonDelawareUSA
| | - Manisha Bansal
- Department of Pediatric Hematology/OncologyNemours Children's HealthJacksonvilleFloridaUSA
| | - Allison S. Bechtel
- Department of Pediatric Hematology/OncologyNemours Children's HealthJacksonvilleFloridaUSA
| | | | - Susan M. Kirwin
- Molecular Diagnostics LaboratoryNemours Children's HealthWilmingtonDelawareUSA
| | - Kathryn V. Blake
- Precision MedicineNemours Children's HealthJacksonvilleFloridaUSA
| | - Nathan D. Seligson
- Precision MedicineNemours Children's HealthJacksonvilleFloridaUSA
- Department of Pharmacotherapy and Translational ResearchThe University of Florida College of PharmacyJacksonvilleFloridaUSA
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Yamashita N, Kawahara M, Imai T, Tatsumi G, Asai-Nishishita A, Andoh A. Loss of Nudt15 thiopurine detoxification increases direct DNA damage in hematopoietic stem cells. Sci Rep 2023; 13:11908. [PMID: 37488179 PMCID: PMC10366091 DOI: 10.1038/s41598-023-38952-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 07/18/2023] [Indexed: 07/26/2023] Open
Abstract
Thiopurines, such as 6-mercaptopurine (6-MP), are widely used as cytotoxic agents and immunosuppressants for leukemia and autoimmune or inflammatory diseases. A nonsynonymous single nucleotide polymorphism (p.Arg139Cys; R139C) of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene causes the loss of thiopurine detoxification, inducing myelosuppression. To understand such hematotoxicity, we investigate the effects of NUDT15 R139C on hematopoietic stem cells (HSCs) upon thiopurine administration. Using previously established Nudt15R138C knock-in mice, which mimic myelosuppression in NUDT15R139C homozygous or heterozygous patients following thiopurine administration, we investigated the numerical changes of HSCs and hematopoietic progenitor cells following 6-MP administration using in vivo flowcytometry and ex vivo HSC expansion. Genes differentially expressed between Nudt15+/+ HSCs and Nudt15R138C/R138C HSCs were identified using RNA-sequencing before the emergence of 6-MP-induced HSC-damage. Gene Ontology (GO) and Transcriptional Regulatory Relationships Unraveled by Sentence-based Text Mining (TRRUST) analyses were performed to elucidate the molecular effects of 6-MP on HSCs. In Nudt15R138C/R138C mice, 6-MP induced exhaustion of HSCs faster than that of multipotent progenitors and as fast as that of myeloid-committed progenitors. Ex vivo-expanded Nudt15R138C/R138C HSCs were dose- and time-dependently damaged by 6-MP. GO analysis identified the DNA damage response and cell cycle process as the most strongly influenced processes in Nudt15R138C/R138C HSCs. TRRUST analysis revealed that the Trp53-regulated transcriptional regulatory network is influenced prior to HSC exhaustion in Nudt15R138C/R138C HSCs. The loss of NUDT15 thiopurine detoxification enhances thiopurine-mediated DNA damage via the Trp53 networks in HSCs. Therefore, caution is required in long-term thiopurine use in patients with NUDT15 R139C in view of its adverse effects on HSCs in the form of DNA damage.
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Affiliation(s)
- Noriaki Yamashita
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Masahiro Kawahara
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan.
| | - Takayuki Imai
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Goichi Tatsumi
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Ai Asai-Nishishita
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Akira Andoh
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
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Suzuki S, Uchiyama K, Motoi Y, Yoshii Y, Inoue Y, Kubota T, Odahara S, Ohtaki Y, Takami S, Ito Z, Sato N, Ohkusa T, Koido S, Saruta M. Analysis of the NUDT15 gene and metabolites of azathioprine in Japanese patients with inflammatory bowel disease. BMC Gastroenterol 2023; 23:239. [PMID: 37454061 DOI: 10.1186/s12876-023-02881-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 07/11/2023] [Indexed: 07/18/2023] Open
Abstract
BACKGROUND Thiopurines continue to play an important role in the treatment of inflammatory bowel disease (IBD). It is well known that thiopurines can cause several adverse reactions. Especially, hematopoietic toxicity may lead to severe agranulocytosis. In a previous prospective study, we investigated the relationship between inosine triphosphate pyrophosphatase (ITPA) c.94c > a polymorphism, 6-thioguanine nucleotide (6-TGN) concentration and toxicity. METHODS To clarify the cause of thiopurine toxicity, we analysed nucleoside disphosphate-linked moiety X-type motif 15 (NUDT15) gene polymorphisms, i.e., R139C, V18I, and V19_V19insGV, and measured 6-mercaptopurines and 6-methylmercaptopurines (6-MMP) using the archived blood samples collected from 49 IBD patients for our previous study. RESULTS The ITPA c.94c > a polymorphism was detected in 19 patients (38.7%, all heterozygous). The R139C polymorphism was found in 10 patients (20.4%, 1 homozygous, 9 heterozygous), V18_V19insGV in 7 patients (14.3%, all heterozygous), and V18I in 2 patients (4.08%, all heterozygous). Although R139C was more strongly associated with leukopenia than c.94c > a, there were no significant correlations with 6-TGN and 6-MMP levels, as for c.94c > a. The leukopenia incidence rates for each gene polymorphism were 0% in those with all wild-type genes, 21.4% for c.94c > a only, 42.9% for NUDT15 polymorphism (s) only, and 80.0% for both polymorphisms. CONCLUSIONS All cases of leukopenia were associated with ITPA c.94c > a and/or polymorphism of NUDT15 and the risk of developing leukopenia was synergistically increased by ITPA and NUDT15 gene polymorphism. However, there was no association between the level of azathioprine metabolites and these polymorphisms.
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Affiliation(s)
- Shizuka Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, 163-1 Kashiwa, Kashiwa-Shi, Chiba, 277-8567, Japan
| | - Kan Uchiyama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, 163-1 Kashiwa, Kashiwa-Shi, Chiba, 277-8567, Japan.
| | - Yutaro Motoi
- Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, F103a, 265-1 Higashijima, Akiha-Ku, Niigata City, 956-8603, Japan
| | - Yuuki Yoshii
- Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, F103a, 265-1 Higashijima, Akiha-Ku, Niigata City, 956-8603, Japan
| | - Yukari Inoue
- Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, F103a, 265-1 Higashijima, Akiha-Ku, Niigata City, 956-8603, Japan
| | - Takahiro Kubota
- Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, F103a, 265-1 Higashijima, Akiha-Ku, Niigata City, 956-8603, Japan
| | - Shunichi Odahara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, 163-1 Kashiwa, Kashiwa-Shi, Chiba, 277-8567, Japan
| | - Yuichiro Ohtaki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, 163-1 Kashiwa, Kashiwa-Shi, Chiba, 277-8567, Japan
| | - Shinichiro Takami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, 163-1 Kashiwa, Kashiwa-Shi, Chiba, 277-8567, Japan
| | - Zensho Ito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, 163-1 Kashiwa, Kashiwa-Shi, Chiba, 277-8567, Japan
| | - Nobuhiro Sato
- Department of Microbiota Research, Juntendo University Graduate School of Medicine, 3-3-1 Hongo, Ochanomizu KS Building 4F 405 Bunkyo-Ku, Tokyo, 113-0033, Japan
| | - Toshifumi Ohkusa
- Department of Microbiota Research, Juntendo University Graduate School of Medicine, 3-3-1 Hongo, Ochanomizu KS Building 4F 405 Bunkyo-Ku, Tokyo, 113-0033, Japan
| | - Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, 163-1 Kashiwa, Kashiwa-Shi, Chiba, 277-8567, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-19-18 Nishishinbashi, Minato-Ku, Tokyo, 105-0003, Japan
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Desai D, Jena A, Sharma V, Hibi T. Time to incorporate preemptive NUDT15 testing before starting thiopurines in inflammatory bowel disease in Asia and beyond: a review. Expert Rev Clin Pharmacol 2023; 16:643-653. [PMID: 37387532 DOI: 10.1080/17512433.2023.2232300] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 06/29/2023] [Indexed: 07/01/2023]
Abstract
INTRODUCTION Thiopurine toxicity is related to genetic polymorphism. Thiopurine methyltransferase (TPMT) variants do not explain thiopurine toxicity in more than half of patients. Asians, despite the low prevalence of TPMT variants, are more susceptible to thiopurine toxicity. Since 2014, studies from many Asian countries have shown a strong association between nucleoside diphosphate-linked moiety X-type motif (NUDT) 15 polymorphism and thiopurine-induced myelotoxicity. AREAS COVERED An English language literature search was performed for TPMT and NUDT15 genetic variants in inflammatory bowel disease and other diseases. This article discusses the merits of preemptive NUDT15 and TPMT testing in Asian and non-Asian IBD populations. EXPERT OPINION The NUDT polymorphism occurs in up to 27% of the Asian and Hispanic population. Hematological toxicity occurs in up to one-third of patients with this genetic variant. Given this, preemptive testing for NUDT15 variant is worthwhile and is probably more cost-effective than TPMT testing in these groups. Prevalence of NUDT15 variants is low in non-Finnish European population, but NUDT15 variants have been linked to myelotoxicity along with TPMT genetic variants. NUDT15 preemptive testing should be considered in the migrant Asian population in Europe and North America and in Caucasian populations who develop myelotoxicity.
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Affiliation(s)
- Devendra Desai
- Division of Gastroenterology, P D Hinduja Hospital, Mumbai, India
| | - Anuraag Jena
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Vishal Sharma
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Toshifumi Hibi
- Center for Advanced IBD Research and Treatment, Kitasato Institute Hospital, Kitasato University, Tokyo, Japan
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Singh M, Bhaskar D, Bhatia P, Thakur R, Sharma P, Bansal D, Jain R, Trehan A. Evaluation of FTO polymorphism in 6-mercaptopurine related intolerance in children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol 2023; 92:51-56. [PMID: 37256334 DOI: 10.1007/s00280-023-04546-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 05/17/2023] [Indexed: 06/01/2023]
Abstract
PURPOSE Thiopurine drugs like 6-Mercaptopurine (6MP) are the cornerstone of maintenance therapy in acute lymphoblastic leukemia (ALL). A recently described variant in alpha-ketoglutarate dependent dioxygenase (FTO) gene has been reported to play an important role in thiopurine induced myelosuppression. METHODS In this study, we genotyped a coding variant (p.Ala134Thr, rs79206939) and an intronic variant (rs16952570) of FTO in 174 Indian children (age ≤ 12 years) with ALL on maintenance phase of chemotherapy and examined correlation with the risk of thiopurine induced myelosuppression and hepatic toxicity. RESULTS The prevalence of FTO-rs16952570 polymorphism was 18.4% (32/174) with 142 (82%) cases having TT genotype, 26 (15%) cases with TC genotype and 6 (3.4%) cases having CC genotype. FTO-rs79206939 was absent and non-polymorphic in our study group. The mean dose of 6-MP during 36 weeks of maintenance of TT, TC and CC carriers of FTO-rs16952570 was 53.7, 53.6 and 54.1 mg/m2/day. Number of patients tolerating starting dose of 60 mg/m2/day was significantly higher in CC (50%) than TT/TC (14%) genotype carrying cases (p = 0.014). However, no statistical significance was observed for total leukocyte count (TLC), absolute neutrophil count (ANC) as well as for platelets counts in patients harboring FTO-rs16952570 TT/TC/CC genotype at 4, 8, 12, 24 and 36 weeks after start of thiopurine therapy. Further, no significant correlation was noted between number of weeks of chemotherapy interruptions or episodes of febrile neutropenia and no evidence of hepatotoxicity was found with the genotype studied. CONCLUSION Polymorphism in FTO-rs16952570 did not show any correlation with thiopurine related toxicity in ALL patients.
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Affiliation(s)
- Minu Singh
- Haematology-Oncology Unit, Department of Paediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Divya Bhaskar
- Haematology-Oncology Unit, Department of Paediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Prateek Bhatia
- Haematology-Oncology Unit, Department of Paediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rozy Thakur
- Haematology-Oncology Unit, Department of Paediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Pankaj Sharma
- Haematology-Oncology Unit, Department of Paediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Deepak Bansal
- Haematology-Oncology Unit, Department of Paediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Richa Jain
- Haematology-Oncology Unit, Department of Paediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Amita Trehan
- Haematology-Oncology Unit, Department of Paediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
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Li P, Chao K, Hu Z, Qin L, Yang T, Mao J, Zhu X, Hu P, Wang X, Gao X, Huang M. Plasma lipidomic profiling of thiopurine-induced leukopenia after NUDT15 genotype-guided dosing in Chinese IBD patients. Front Nutr 2023; 10:1138506. [PMID: 37441519 PMCID: PMC10333543 DOI: 10.3389/fnut.2023.1138506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 05/10/2023] [Indexed: 07/15/2023] Open
Abstract
Introduction Thiopurines, azathiopurine (AZA) and mercaptopurine (6-MP) have been regularly used in the treatment of inflammatory bowel disease (IBD). Despite optimized dosage adjustment based on the NUDT15 genotypes, some patients still discontinue or change treatment regimens due to thiopurine-induced leukopenia. Methods We proposed a prospective observational study of lipidomics to reveal the lipids perturbations associated with thiopurine-induced leukopenia. One hundred and twenty-seven IBD participants treated with thiopurine were enrolled, twenty-seven of which have developed thiopurine-induced leucopenia. Plasma lipid profiles were measured using Ultra-High-Performance Liquid Chromatography-Tandem Q-Exactive. Lipidomic alterations were validated with an independent validation cohort (leukopenia n = 26, non-leukopenia n = 74). Results Using univariate and multivariate analysis, there were 16 lipid species from four lipid classes, triglyceride (n = 11), sphingomyelin (n = 1), phosphatidylcholine (n = 1) and lactosylceramide (n = 3) identified. Based on machine learning feature reduction and variable screening strategies, the random forest algorithm established by six lipids showed an excellent performance to distinguish the leukopenia group from the normal group, with a model accuracy of 95.28% (discovery cohort), 79.00% (validation cohort) and an area under the receiver operating characteristic (ROC) curve (ROC-AUC) of 0.9989 (discovery cohort), 0.8098 (validation cohort). Discussion Our novel findings suggested that lipidomic provided unique insights into formulating individualized medication strategies for thiopurines in IBD patients.
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Affiliation(s)
- Pan Li
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Kang Chao
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, Guangzhou, China
| | - Zhanhua Hu
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Lulu Qin
- School of Pharmaceutical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Ting Yang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Jing Mao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Xia Zhu
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, Guangzhou, China
| | - Pinjin Hu
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, Guangzhou, China
| | - Xueding Wang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Xiang Gao
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, Guangzhou, China
| | - Min Huang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
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Chikondowa P, Munkombwe D, Chikwambi Z, Kuona P, Masimirembwa C. Pharmacogenetics of 6-mercaptopurine in a black Zimbabwean cohort treated for acute lymphoblastic leukaemia. Pharmacogenomics 2023; 24:449-457. [PMID: 37248698 PMCID: PMC10463210 DOI: 10.2217/pgs-2023-0026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 05/16/2023] [Indexed: 05/31/2023] Open
Abstract
Background: 6-mercaptopurine usage is associated with myelotoxicity and increased risk in patients carrying metabolism-related genetic variations. This study aimed to determine the frequency of candidate gene polymorphisms and their association with 6-mercaptopurine intolerance. Methods: A total of 41 patients on acute lymphoblastic leukaemia treatment were genotyped for TPMT and NUDT15 (rs116855232) alleles, and their association with dose intensity was analyzed. Results: The defective TPMT*3C allele frequency was 9.8%. The median maintenance dose intensity for TPMT*1/*3C participants was considerably lower (47%) when compared with the TPMT*1/*1 wild-type (77%), although not statistically significant. Conclusion: This is the first pharmacogenetics study carried out in a black Zimbabwean leukemia patient cohort. The high defective TPMT*3C (9.8%) allele frequency points to the potential utility of pharmacogenetics testing for safe usage of 6-mercaptopurine in this population.
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Affiliation(s)
- Pageneck Chikondowa
- Department of Genomic Medicine, African Institute of Biomedical Science & Technology (AiBST), Harare, Zimbabwe
- Department of Biotechnology, School of Health Science & Technology, Chinhoyi University of Technology, Chinhoyi, Zimbabwe
| | - Derick Munkombwe
- Department of Genomic Medicine, African Institute of Biomedical Science & Technology (AiBST), Harare, Zimbabwe
- Department of Pharmacy, School of Health Sciences, University of Zambia, Lusaka, 10101, Zambia
| | - Zedias Chikwambi
- Department of Genomic Medicine, African Institute of Biomedical Science & Technology (AiBST), Harare, Zimbabwe
- Department of Biotechnology, School of Health Science & Technology, Chinhoyi University of Technology, Chinhoyi, Zimbabwe
| | - Patience Kuona
- Department of Paediatrics, Faculty of Medicine & Health Sciences, University of Zimbabwe, Harare, Zimbabwe
| | - Collen Masimirembwa
- Department of Genomic Medicine, African Institute of Biomedical Science & Technology (AiBST), Harare, Zimbabwe
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Kabbani D, Akika R, Wahid A, Daly AK, Cascorbi I, Zgheib NK. Pharmacogenomics in practice: a review and implementation guide. Front Pharmacol 2023; 14:1189976. [PMID: 37274118 PMCID: PMC10233068 DOI: 10.3389/fphar.2023.1189976] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 05/03/2023] [Indexed: 06/06/2023] Open
Abstract
Considerable efforts have been exerted to implement Pharmacogenomics (PGx), the study of interindividual variations in DNA sequence related to drug response, into routine clinical practice. In this article, we first briefly describe PGx and its role in improving treatment outcomes. We then propose an approach to initiate clinical PGx in the hospital setting. One should first evaluate the available PGx evidence, review the most relevant drugs, and narrow down to the most actionable drug-gene pairs and related variant alleles. This is done based on data curated and evaluated by experts such as the pharmacogenomics knowledge implementation (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC), as well as drug regulatory authorities such as the US Food and Drug Administration (FDA) and European Medicinal Agency (EMA). The next step is to differentiate reactive point of care from preemptive testing and decide on the genotyping strategy being a candidate or panel testing, each of which has its pros and cons, then work out the best way to interpret and report PGx test results with the option of integration into electronic health records and clinical decision support systems. After test authorization or testing requirements by the government or drug regulators, putting the plan into action involves several stakeholders, with the hospital leadership supporting the process and communicating with payers, the pharmacy and therapeutics committee leading the process in collaboration with the hospital laboratory and information technology department, and healthcare providers (HCPs) ordering the test, understanding the results, making the appropriate therapeutic decisions, and explaining them to the patient. We conclude by recommending some strategies to further advance the implementation of PGx in practice, such as the need to educate HCPs and patients, and to push for more tests' reimbursement. We also guide the reader to available PGx resources and examples of PGx implementation programs and initiatives.
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Affiliation(s)
- Danya Kabbani
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Reem Akika
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Ahmed Wahid
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Ann K. Daly
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Ingolf Cascorbi
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Nathalie Khoueiry Zgheib
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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The influence of NUDT15 variants on 6-mercaptopurine-induced neutropenia in Vietnamese pediatric acute lymphoblastic leukemia. HGG ADVANCES 2023; 4:100183. [PMID: 36873097 PMCID: PMC9974434 DOI: 10.1016/j.xhgg.2023.100183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
6-Mercaptopurine (6-MP) serves as the backbone of maintenance therapy in acute lymphoblastic leukemia. The nucleoside diphosphate-linked moiety X-type motif 15 genes (NUDT15) affects the metabolism of 6-MP and thiopurine-related neutropenia in the Asian population. This study reports the influence of these variants on 6MP-induced neutropenia in children with acute lymphoblastic leukemia (ALL). A total of 102 children were enrolled in this retrospective cohort study. NUDT15 variants on exon 1 and exon 3 were identified by Sanger sequencing. We divided the intermediate metabolizer group and the normal metabolizer group base on NUDT15 diplotypes. During the first 3 months of maintenance treatment, medical reports measured treatment-related toxicity (neutropenia) and 6-MP dose decreases. NUDT15 genotyping showed two categories of mutations: wild type (75.5%) and heterozygous variant (24.5%). Neutropenia during the early phase of maintenance therapy in the intermediate metabolizer group (68%) was significantly higher than the normal metabolizer group (18.2%) with 10-fold greater odds. Especially, the c.415C>T heterozygous variant was extremely associated with neutropenia compared with the C>C genotype (odds ratio [OR]: 12; 95% confidence interval [CI]: 3.5-41.7). The tolerated doses of 6-MP after the first 3 months of maintenance therapy related to the intermediate metabolizer group and the normal metabolizer group were 48.7 and 64.3 mg/m2/day, respectively (p < 0.001). One-fourth of individuals had NUDT15 variations. All NUDT15 heterozygous mutations cause neutropenia and need 6-MP dose optimization. Given the frequency of NUDT15 mutations in Vietnamese children and their connection with early neutropenia, testing is indicated.
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Larkin T, Kashif R, Elsayed AH, Greer B, Mangrola K, Raffiee R, Nguyen N, Shastri V, Horn B, Lamba JK. Polygenic Pharmacogenomic Markers as Predictors of Toxicity Phenotypes in the Treatment of Acute Lymphoblastic Leukemia: A Single-Center Study. JCO Precis Oncol 2023; 7:e2200580. [PMID: 36952646 PMCID: PMC10309546 DOI: 10.1200/po.22.00580] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 01/31/2023] [Indexed: 03/25/2023] Open
Abstract
PURPOSE Acute lymphoblastic leukemia (ALL) is the most prevalent cause of childhood cancer and requires a long course of therapy consisting of three primary phases with interval intensification blocks. Although these phases are necessary to achieve remission, the primary chemotherapeutic agents have potentially serious toxicities, which may lead to delays or discontinuations of therapy. The purpose of this study was to perform a comprehensive pharmacogenomic evaluation of common antileukemic agents and develop a polygenic toxicity risk score predictive of the most common toxicities observed during ALL treatment. METHODS This cross-sectional study included 75 patients with pediatric ALL treated between 2012 and 2020 at the University of Florida. Toxicity data were collected within 100 days of initiation of therapy using CTCAE v4.0 for toxicity grading. For pharmacogenomic evaluation, single-nucleotide polymorphisms (SNPs) and genes were selected from previous reports or PharmGKB database. 116 unique SNPs were evaluated for incidence of various toxicities. A multivariable multi-SNP modeling for up to 3-SNP combination was performed to develop a polygenic toxicity risk score of prognostic value. RESULTS We identified several SNPs predictive of toxicity phenotypes in univariate analysis. Further multivariable SNP-SNP combination analysis suggest that susceptibility to chemotherapy-induced toxicities is likely multigenic in nature. For 3-SNPscore models, patients with high scores experienced increased risk of GI (P = 2.07E-05, 3 SNPs: TYMS-rs151264360/FPGS-rs1544105/GSTM1-GSTM5-rs3754446), neurologic (P = .0005, 3 SNPs: DCTD-rs6829021/SLC28A3-rs17343066/CTPS1-rs12067645), endocrine (P = 4.77E-08, 3 SNPs: AKR1C3-rs1937840/TYMS-rs2853539/CTH-rs648743), and heme toxicities (P = .053, 3 SNPs: CYP3A5-rs776746/ABCB1-rs4148737/CTPS1-rs12067645). CONCLUSION Our results imply that instead of a single-SNP approach, SNP-SNP combinations in multiple genes in drug pathways increases the robustness of prediction of toxicity. These results further provide promising SNP models that can help establish clinically relevant biomarkers allowing for greater individualization of cancer therapy to maximize efficacy and minimize toxicity for each patient.
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Affiliation(s)
- Trisha Larkin
- Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL
- St Joseph's Children's Hospital/BayCare Medical Group, Tampa, FL
| | - Reema Kashif
- Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL
| | - Abdelrahman H. Elsayed
- Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL
| | - Beate Greer
- Pediatrics Division, UF Health Cancer Center, University of Florida, Gainesville, FL
| | - Karna Mangrola
- Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL
| | - Roya Raffiee
- Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL
| | - Nam Nguyen
- Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL
| | - Vivek Shastri
- Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL
| | - Biljana Horn
- Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL
| | - Jatinder K. Lamba
- Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL
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Pharmacogenetic Aspects of Drug Metabolizing Enzymes and Transporters in Pediatric Medicine: Study Progress, Clinical Practice and Future Perspectives. Paediatr Drugs 2023; 25:301-319. [PMID: 36707496 DOI: 10.1007/s40272-023-00560-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/09/2023] [Indexed: 01/28/2023]
Abstract
As the activity of certain drug metabolizing enzymes or transporter proteins can vary with age, the effect of ontogenetic and genetic variation on the activity of these enzymes is critical for the accurate prediction of treatment outcomes and toxicity in children. This makes pharmacogenetic research in pediatrics particularly important and urgently needed, but also challenging. This review summarizes pharmacogenetic studies on the effects of genetic polymorphisms on pharmacokinetic parameters and clinical outcomes in pediatric populations for certain drugs, which are commonly prescribed by clinicians across multiple therapeutic areas in a general hospital, organized from those with the most to the least pediatric evidence among each drug category. We also further discuss the research status of the gene-guided dosing regimens and clinical implementation of pediatric pharmacogenetics. More and more drug-gene interactions are demonstrated to have clinical validity for children, and pharmacogenomics in pediatrics have shown evidence-based benefits to enhance the efficacy and precision of existing drug dosing regimens in several therapeutic areas. However, the most important limitation to the implementation is the lack of high-quality, rigorous pediatric prospective clinical studies, so adequately powered interventional clinical trials that support incorporation of pharmacogenetics into the care of children are still needed.
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Allele-specific polymerase chain reaction can determine the diplotype of NUDT15 variants in patients with childhood acute lymphoblastic Leukemia. Sci Rep 2023; 13:490. [PMID: 36627439 PMCID: PMC9832159 DOI: 10.1038/s41598-023-27720-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 01/06/2023] [Indexed: 01/12/2023] Open
Abstract
Mercaptopurine intolerance is an adverse effect of mercaptopurine administration in pediatric patients with acute lymphoblastic leukemia (ALL). NUDT15 variants have emerged as major determinants of mercaptopurine intolerance, especially in the Asian population. Two variants, c.55_56insGAGTCG in exon 1 and c.415C > T in exon 3, were commonly detected in the same allele, named NUDT15*1/*2. Although rare, compound heterozygous mutations also occur, with the two variants on different alleles (NUDT15*3/*6), which may confer tolerance to considerably lesser mercaptopurine dosage. Sanger sequencing or pyrosequencing can determine the NUDT15 variants but not the phase. Here, we designed an allele-specific PCR (AS-PCR) with locked nucleic acid-modified primers. A cohort of 63 patients harboring heterozygous c.55_56insGAGTCG and c.415C > T NUDT15 variations was selected for haplotyping using AS-PCR. Of the 63 patients, 60 harbored the NUDT15*1/*2 variant and three harbored compound heterozygous mutations, including two NUDT15*3/*6 and one NUDT15*2/*7 variants. These findings suggest that AS-PCR can determine NUDT15 diplotype and identify patients with compound heterozygous NUDT15 variants, which may enable precise genetic diagnosis of NUDT15. Nevertheless, a larger clinical trial is required to understand the clinical significance of NUDT15*3/*6 in pediatric patients with ALL because of its low incidence rate and challenges in detecting this variant.
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Hosokawa H, Kitazawa H, Akita N, Yoshida N, Hama A. Severe myelosuppression involving HPV-B19 infection and NUDT15 polymorphisms during therapy for LCH. Pediatr Int 2023; 65:e15669. [PMID: 37888780 DOI: 10.1111/ped.15669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 08/23/2023] [Accepted: 08/30/2023] [Indexed: 10/28/2023]
Affiliation(s)
- Hiroki Hosokawa
- Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Aichi Medical Center Nagoya First Hospital, Nagoya, Japan
| | - Hironobu Kitazawa
- Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Aichi Medical Center Nagoya First Hospital, Nagoya, Japan
| | - Nobuhiro Akita
- Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Aichi Medical Center Nagoya First Hospital, Nagoya, Japan
| | - Nao Yoshida
- Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Aichi Medical Center Nagoya First Hospital, Nagoya, Japan
| | - Asahito Hama
- Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Aichi Medical Center Nagoya First Hospital, Nagoya, Japan
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Helleday T. Mitotic MTH1 Inhibitors in Treatment of Cancer. Cancer Treat Res 2023; 186:223-237. [PMID: 37978139 DOI: 10.1007/978-3-031-30065-3_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2023]
Abstract
The DNA damage response (DDR) protein MTH1 is sanitising the oxidized dNTP pool and preventing incorporation of oxidative damage into DNA and has an emerging role in mitosis. It is a stress-induced protein and often found to be overexpressed in cancer. Mitotic MTH1 inhibitors arrest cells in mitosis and result in incorporation of oxidative damage into DNA and selective killing of cancer cells. Here, I discuss the leading mitotic MTH1 inhibitor TH1579 (OXC-101, karonudib), now being evaluated in clinical trials, and describe its dual effect on mitosis and incorporation of oxidative DNA damage in cancer cells. I describe why MTH1 inhibitors that solely inhibits the enzyme activity fail to kill cancer cells and discuss if MTH1 is a valid target for cancer treatment. I discuss emerging roles of MTH1 in regulating tubulin polymerisation and mitosis and the necessity of developing the basic science insights along with translational efforts. I also give a perspective on how edgetic perturbation is making target validation difficult in the DDR field.
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Affiliation(s)
- Thomas Helleday
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
- Department of Oncology and Metabolism, Weston Park Cancer Centre, University of Sheffield, Sheffield, UK.
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Alqahtani A, Alhousari D, Ali A, Yaghmour G, Orgel E, Curran E, Stock W, Bhojwani D, Alachkar H. Asparaginase toxicity in Hispanic adult and pediatric patients with acute lymphoblastic leukemia: current understanding. Expert Opin Drug Metab Toxicol 2023; 19:357-366. [PMID: 37410014 PMCID: PMC11516125 DOI: 10.1080/17425255.2023.2233412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 07/03/2023] [Indexed: 07/07/2023]
Abstract
INTRODUCTION Asparaginase is essential to chemotherapy regimens for acute lymphoblastic leukemia (ALL). Survival of patients with ALL has improved since incorporating asparaginase into chemotherapy backbones. Hispanic patients have a higher incidence of ALL than other ethnicities and suffer inferior outcomes. The inferior outcome of Hispanics is due to several factors, including the increased incidence of high-risk genetic subtypes and susceptibility to treatment-related toxicity. AREAS COVERED We summarize the current knowledge of asparaginase-related toxicity by comparing their incidence between Hispanic and non-Hispanic patients. These toxicities include hypersensitivity, hepatotoxicity, pancreatitis, thrombosis, and hypertriglyceridemia. The PubMed database and Google Scholar were used to search for this review from October 2022 to June 2023. EXPERT OPINION Except for hepatotoxicity and hypertriglyceridemia secondary to asparaginase-based treatments, which may develop more frequently among Hispanic patients with ALL, other toxicities were comparable between Hispanic and non-Hispanic patients. Nevertheless, studies with larger cohorts and more accurate capturing of Hispanic ethnicity should be conducted to fill the gaps in the current knowledge.
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Affiliation(s)
- Amani Alqahtani
- School of Pharmacy, University of Southern California, Los Angeles, CA, USA
- Department of Clinical pharmacy, School of Pharmacy, Najran University, Najran, Saudi Arabia
| | - Diala Alhousari
- School of Pharmacy, University of Southern California, Los Angeles, CA, USA
| | - Amir Ali
- USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA
| | - George Yaghmour
- USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA
| | - Etan Orgel
- USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA
- Cancer and Blood Disease Institute, Children’s Hospital of Los Angeles, Los Angeles, CA, USA
| | - Emily Curran
- The Department of Medicine, Section of Hematology & Oncology at the University of Cincinnati College of Medicine
| | - Wendy Stock
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Deepa Bhojwani
- USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA
- Cancer and Blood Disease Institute, Children’s Hospital of Los Angeles, Los Angeles, CA, USA
| | - Houda Alachkar
- School of Pharmacy, University of Southern California, Los Angeles, CA, USA
- USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA
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Gupta N, Magatha LS, Jayaraman D, Scott JX, Antony SB, Koshy T. Mercaptopurine induced myelosuppression in a child with a NUDT15 rs116855232 homozygous variant. J Oncol Pharm Pract 2022:10781552221137709. [DOI: 10.1177/10781552221137709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Introduction Mercaptopurine (6-MP) is the backbone of the consolidation and maintenance therapy for paediatric acute lymphoblastic leukaemia (ALL). Nevertheless, it can cause critical myelosuppression. Predicting adverse reactions to 6-MP often involves the investigation of pharmacogenetic variants; in particular thiopurine S-methyltransferase ( TPMT) and nudix hydrolase 15 ( NUDT15). Lately, NUDT15 variants have been shown to play a significant pharmacogenetic role in predicting 6-MP intolerance in children of Asian descent. Case Report We present a six-year-old male child of Indian origin with persistent cytopenia after treatment. This prompted targeted sequencing of the genes TPMT and NUD15. The results revealed two copies of the variant of NUD15 rs116855232, that is, NUDT15*2 genotype. Management and Outcome Since the NUDT15*2 allele classified the patient as a poor metabolizer, he was restarted on a low dose of 6-MP, which he tolerated. Discussion Individuals with the NUDT15*2allele (*2/*2 genotype) are poor metabolizers of thiopurines which results in an adverse reaction to 6-MP. About 3.5% of Indians show variations in the TPMT gene as compared to 19.4% variations observed in NUDT15, which makes the latter a more reliable disease marker.
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Affiliation(s)
- Navya Gupta
- Pediatic Hemato-oncology Unit, Department of Pediatrics, Sri Ramachandra Medical College and Research Institute, Porur, Chennai, India
| | - Latha Sneha Magatha
- Pediatic Hemato-oncology Unit, Department of Pediatrics, Sri Ramachandra Medical College and Research Institute, Porur, Chennai, India
| | - Dhaarani Jayaraman
- Pediatic Hemato-oncology Unit, Department of Pediatrics, Sri Ramachandra Medical College and Research Institute, Porur, Chennai, India
| | - Julius Xavier Scott
- Pediatic Hemato-oncology Unit, Department of Pediatrics, Sri Ramachandra Medical College and Research Institute, Porur, Chennai, India
| | - Sharon Benita Antony
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Science and Technology, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, India
| | - Teena Koshy
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Science and Technology, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, India
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