Ravi Ramalingam1, Harpreet Kaur1, Julius Xavier Scott2, Latha M Sneha2, Ganeshprasad Arunkumar3, Arathi Srinivasan4, Solomon F D Paul5. 1. Department of Human Genetics, Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, India. 2. Department of Pediatric Oncology, Sri Ramachandra Institute of Higher Education and Research, Chennai, India. 3. MedGenome Labs Ltd., Bangalore, India. 4. Department of Pediatric Oncology, Kanchi Kamakoti Child Trust Hospital, Chennai, Tamil Nadu, India. 5. Department of Human Genetics, Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, India. paul@sriramachandra.edu.in.
Abstract
PURPOSE: Pediatric acute lymphoblastic leukemia (pALL) patients have better overall survival and methotrexate (MTX) is an effective drug used in their treatment. However, the treatment-related adverse effects (TRAEs) have a bigger impact on the therapy. In this study, we have evaluated the association of polymorphisms in genes encoding proteins engaged in MTX metabolism, and the cytogenetic aberrations with TRAEs. METHODS: A total of 115 patients between the age of 1 and 18 years (average: 6.6) under maintenance therapy were selected for the study. SLC19A1 (c.80G > A), MTHFR (c.677C > T; c.1298A > C), and TYMS (c.*450_*455del) genotypes were determined using PCR techniques and Sanger sequencing. Cytogenetic and SNP findings were analyzed for any association with the reported toxicities using odds ratio, chi-square test, multifactor dimensionality reduction (MDR) analysis for synergistic effect and, multinomial logistic regression analysis for the likelihood of adverse events. RESULTS: Among the evaluated genetic variations, SLC19A1 (c.80G > A) was significantly associated with TRAEs (OR = 5.71, p = 0.002). Multinomial logistic regression analysis (chi-sq = 16.64, p < 0.001) and MDR analysis (chi-sq = 10.51 p < 0.001) confirmed the finding. On the other hand, no significant association was observed between adverse events and any specific cytogenetic aberration. CONCLUSION: SLC19A1 facilitates the import of cyclic dinucleotides and reduced folates, evaluating genotypes in this gene can help in better management of patients on methotrexate treatment. Assessing a broader gene panel can help in finding more associated markers and delivering personalized medicine to the patients.
PURPOSE: Pediatric acute lymphoblastic leukemia (pALL) patients have better overall survival and methotrexate (MTX) is an effective drug used in their treatment. However, the treatment-related adverse effects (TRAEs) have a bigger impact on the therapy. In this study, we have evaluated the association of polymorphisms in genes encoding proteins engaged in MTX metabolism, and the cytogenetic aberrations with TRAEs. METHODS: A total of 115 patients between the age of 1 and 18 years (average: 6.6) under maintenance therapy were selected for the study. SLC19A1 (c.80G > A), MTHFR (c.677C > T; c.1298A > C), and TYMS (c.*450_*455del) genotypes were determined using PCR techniques and Sanger sequencing. Cytogenetic and SNP findings were analyzed for any association with the reported toxicities using odds ratio, chi-square test, multifactor dimensionality reduction (MDR) analysis for synergistic effect and, multinomial logistic regression analysis for the likelihood of adverse events. RESULTS: Among the evaluated genetic variations, SLC19A1 (c.80G > A) was significantly associated with TRAEs (OR = 5.71, p = 0.002). Multinomial logistic regression analysis (chi-sq = 16.64, p < 0.001) and MDR analysis (chi-sq = 10.51 p < 0.001) confirmed the finding. On the other hand, no significant association was observed between adverse events and any specific cytogenetic aberration. CONCLUSION: SLC19A1 facilitates the import of cyclic dinucleotides and reduced folates, evaluating genotypes in this gene can help in better management of patients on methotrexate treatment. Assessing a broader gene panel can help in finding more associated markers and delivering personalized medicine to the patients.
Authors: J Salazar; A Altés; E del Río; J Estella; S Rives; M Tasso; A Navajas; J Molina; M Villa; J L Vivanco; M Torrent; M Baiget; I Badell Journal: Pharmacogenomics J Date: 2011-07-12 Impact factor: 3.550
Authors: Dyego O de Miranda; Jemima E X S Barros; Maria Madalena S Vieira; Elker L S Lima; Vera L L Moraes; Helker A da Silva; Helder L B O Garcia; Cássia A Lima; Adriana V Gomes; Neide Santos; Maria T C Muniz Journal: Mol Biol Rep Date: 2014-04-27 Impact factor: 2.316