Impact of Pharmacogenetics on High-Dose Methotrexate Toxicity in Pediatric Oncology
<b>Background</b>: Childhood cancers represent a heterogeneous group of malignancies and remain one of the leading causes of mortality among children under 14 years of age, ranking second only to accidental injuries, and fourth among individuals aged 15 to 19 years. Despite notable impro...
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| author | Luciana Maria Marangoni-Iglecias Almudena Sánchez-Martin Laura Elena Pineda-Lancheros Yasmín Cura Noelia Marquez-Pete José María Gálvez-Navas Nerea Báez-Gutiérrez Adrián Manuel de La Jara-Vera Emilia Urrutia-Maldonado Cristina Pérez-Ramírez Alberto Jiménez-Morales |
| author_facet | Luciana Maria Marangoni-Iglecias Almudena Sánchez-Martin Laura Elena Pineda-Lancheros Yasmín Cura Noelia Marquez-Pete José María Gálvez-Navas Nerea Báez-Gutiérrez Adrián Manuel de La Jara-Vera Emilia Urrutia-Maldonado Cristina Pérez-Ramírez Alberto Jiménez-Morales |
| author_sort | Luciana Maria Marangoni-Iglecias |
| collection | DOAJ |
| description | <b>Background</b>: Childhood cancers represent a heterogeneous group of malignancies and remain one of the leading causes of mortality among children under 14 years of age, ranking second only to accidental injuries, and fourth among individuals aged 15 to 19 years. Despite notable improvements in cure rates, a substantial proportion of patients experience acute or long-term toxicities associated with treatment. Methotrexate (MTX), a chemotherapeutic agent, has been employed effectively for over six decades in the management of pediatric malignancies. High-dose methotrexate constitutes a cornerstone of pediatric cancer therapy; however, its clinical utility is frequently constrained by dose-limiting toxicities. <b>Objectives:</b> This study investigates the impact of genetic polymorphisms in genes involved in nucleotide metabolism, as well as methotrexate and folate metabolic pathways, on treatment-related toxicity in childhood cancer. <b>Methods:</b> Using real-time polymerase chain reaction, 14 polymorphisms across 12 genes were analyzed in a cohort of 107 patients. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events v. 5.0. <b>Results:</b> Multivariate logistic regression analysis revealed that the male sex (<i>p</i> = 0.3) and the AA genotype of <i>MTHFD1</i> rs2236225 were associated with grade III–IV gastrointestinal toxicity (<i>p</i> = 0.03), while the A allele of <i>MTHFR</i> rs1801133 and the AA genotype of <i>GSTP1</i> rs1695 were associated with grade I–IV hematologic toxicity (<i>p</i> < 0.01 and <i>p</i> = 0.02, respectively). <b>Conclusions:</b> High-dose methotrexate (HDMTX) is a critical agent in the treatment of childhood cancers. Our findings suggest that genetic polymorphisms within methotrexate and folate metabolic pathways may serve as potential predictive biomarkers of treatment-related toxicity. |
| format | Article |
| id | doaj-art-e8368e30cbee4f4db537a24c064406b1 |
| institution | OA Journals |
| issn | 1999-4923 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
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| series | Pharmaceutics |
| spelling | doaj-art-e8368e30cbee4f4db537a24c064406b12025-08-20T02:33:58ZengMDPI AGPharmaceutics1999-49232025-04-0117558510.3390/pharmaceutics17050585Impact of Pharmacogenetics on High-Dose Methotrexate Toxicity in Pediatric OncologyLuciana Maria Marangoni-Iglecias0Almudena Sánchez-Martin1Laura Elena Pineda-Lancheros2Yasmín Cura3Noelia Marquez-Pete4José María Gálvez-Navas5Nerea Báez-Gutiérrez6Adrián Manuel de La Jara-Vera7Emilia Urrutia-Maldonado8Cristina Pérez-Ramírez9Alberto Jiménez-Morales10Clinical Analysis Laboratory Unit, Hospital Universitário Maria Aparecida Pedrossian HUMAP-UFMS. Av. Sen. Filinto Müler, 355-Vila Ipiranga, Campo Grande 79080-190, BrazilPharmacy Service, Pharmacogenetics Unit, University Hospital Virgen de las Nieves, Avda. de las Fuerzas Armadas 2, 18004 Granada, SpainPharmacogenetics Unit, Pharmacy Service, Virgen de las Nieves University Hospital, 18014 Granada, SpainPharmacy Service, Pharmacogenetics Unit, University Hospital Virgen de las Nieves, Avda. de las Fuerzas Armadas 2, 18004 Granada, SpainPharmacy Service, Pharmacogenetics Unit, University Hospital Virgen de las Nieves, Avda. de las Fuerzas Armadas 2, 18004 Granada, SpainInstituto de Investigación Biosanitaria ibs.GRANADA, Avda. de Madrid 15, 18012 Granada, SpainPharmacy Service Hospital Virgen del Rocío, Avenida De Manuel Siurot S/n, 41013 Seville, SpainPharmacy Service, Pharmacogenetics Unit, University Hospital Virgen de las Nieves, Avda. de las Fuerzas Armadas 2, 18004 Granada, SpainAssistant Physician, University Hospital Virgen de las Nieves, Avda. de las Fuerzas Armadas 2, 18004 Granada, SpainPharmacy Service, Pharmacogenetics Unit, University Hospital Virgen de las Nieves, Avda. de las Fuerzas Armadas 2, 18004 Granada, SpainPharmacy Service, Pharmacogenetics Unit, University Hospital Virgen de las Nieves, Avda. de las Fuerzas Armadas 2, 18004 Granada, Spain<b>Background</b>: Childhood cancers represent a heterogeneous group of malignancies and remain one of the leading causes of mortality among children under 14 years of age, ranking second only to accidental injuries, and fourth among individuals aged 15 to 19 years. Despite notable improvements in cure rates, a substantial proportion of patients experience acute or long-term toxicities associated with treatment. Methotrexate (MTX), a chemotherapeutic agent, has been employed effectively for over six decades in the management of pediatric malignancies. High-dose methotrexate constitutes a cornerstone of pediatric cancer therapy; however, its clinical utility is frequently constrained by dose-limiting toxicities. <b>Objectives:</b> This study investigates the impact of genetic polymorphisms in genes involved in nucleotide metabolism, as well as methotrexate and folate metabolic pathways, on treatment-related toxicity in childhood cancer. <b>Methods:</b> Using real-time polymerase chain reaction, 14 polymorphisms across 12 genes were analyzed in a cohort of 107 patients. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events v. 5.0. <b>Results:</b> Multivariate logistic regression analysis revealed that the male sex (<i>p</i> = 0.3) and the AA genotype of <i>MTHFD1</i> rs2236225 were associated with grade III–IV gastrointestinal toxicity (<i>p</i> = 0.03), while the A allele of <i>MTHFR</i> rs1801133 and the AA genotype of <i>GSTP1</i> rs1695 were associated with grade I–IV hematologic toxicity (<i>p</i> < 0.01 and <i>p</i> = 0.02, respectively). <b>Conclusions:</b> High-dose methotrexate (HDMTX) is a critical agent in the treatment of childhood cancers. Our findings suggest that genetic polymorphisms within methotrexate and folate metabolic pathways may serve as potential predictive biomarkers of treatment-related toxicity.https://www.mdpi.com/1999-4923/17/5/585HDMTXgenetic polymorphismschildhood cancerpharmacogenetics |
| spellingShingle | Luciana Maria Marangoni-Iglecias Almudena Sánchez-Martin Laura Elena Pineda-Lancheros Yasmín Cura Noelia Marquez-Pete José María Gálvez-Navas Nerea Báez-Gutiérrez Adrián Manuel de La Jara-Vera Emilia Urrutia-Maldonado Cristina Pérez-Ramírez Alberto Jiménez-Morales Impact of Pharmacogenetics on High-Dose Methotrexate Toxicity in Pediatric Oncology Pharmaceutics HDMTX genetic polymorphisms childhood cancer pharmacogenetics |
| title | Impact of Pharmacogenetics on High-Dose Methotrexate Toxicity in Pediatric Oncology |
| title_full | Impact of Pharmacogenetics on High-Dose Methotrexate Toxicity in Pediatric Oncology |
| title_fullStr | Impact of Pharmacogenetics on High-Dose Methotrexate Toxicity in Pediatric Oncology |
| title_full_unstemmed | Impact of Pharmacogenetics on High-Dose Methotrexate Toxicity in Pediatric Oncology |
| title_short | Impact of Pharmacogenetics on High-Dose Methotrexate Toxicity in Pediatric Oncology |
| title_sort | impact of pharmacogenetics on high dose methotrexate toxicity in pediatric oncology |
| topic | HDMTX genetic polymorphisms childhood cancer pharmacogenetics |
| url | https://www.mdpi.com/1999-4923/17/5/585 |
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