Rihwa Choi1,2, Insuk Sohn3, Min-Ji Kim3, Hye In Woo1, Ji Won Lee4, Youngeun Ma4,5, Eun Sang Yi4,6, Hong Hoe Koo4, Soo-Youn Lee1,7. 1. Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 2. Department of Laboratory Medicine, Green Cross Laboratories, Yongin, Gyeonggi, Republic of Korea. 3. Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea. 4. Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 5. Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea. 6. Department of Pediatrics, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea. 7. Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Abstract
AIMS: We aimed to investigate the impact of various genetic polymorphisms affecting thiopurine metabolism pathways and toxicity in paediatric acute lymphoblastic leukaemia patients for the first time in Korea. METHODS: From May 2006 to September 2016, 139 paediatric acute lymphoblastic leukaemia patients treated with combination chemotherapy including 6-mercaptopurine were included in the study. One hundred and twenty-three variants in 43 genes, including TMPT and NUDT15, were screened using targeted genotyping, such as a MassARRAY system, direct sequencing and polymerase chain reaction-restriction fragment length polymorphism methods. Among the polymorphisms screened, 103 polymorphisms of 43 genes were included for further analyses. RESULTS: The genetic polymorphisms in the ABCC4, AHCY, ATIC, FAM8A6P, GART, GNG2, GSTA1, MTHFD1, MTHFR, NUDT15, PACSIN2, TYMS and XDH genes, and an intronic polymorphism between HIVEP2 and AIG1, and TPMT genotype were associated with thiopurine metabolism (P < 0.05). Genetic polymorphisms in the ABCC4, ADK, ATIC, GART, GMPS, GSTP1, IMPDH1, ITPA, KCNMA1, MOCOS, MTRR, NUDT15, SLC19A1, SLC28A3, SLC29A1, SLCO1B1, TYMP and XDH genes were associated with thiopurine-related toxicities; neutropenia, hepatotoxicity and treatment interruption (P < 0.05). CONCLUSIONS: Findings of this study may provide basic knowledge for personalized medicine for thiopurinxe treatment in paediatric acute lymphoblastic leukaemia patients.
AIMS: We aimed to investigate the impact of various genetic polymorphisms affecting thiopurine metabolism pathways and toxicity in paediatric acute lymphoblastic leukaemiapatients for the first time in Korea. METHODS: From May 2006 to September 2016, 139 paediatric acute lymphoblastic leukaemiapatients treated with combination chemotherapy including 6-mercaptopurine were included in the study. One hundred and twenty-three variants in 43 genes, including TMPT and NUDT15, were screened using targeted genotyping, such as a MassARRAY system, direct sequencing and polymerase chain reaction-restriction fragment length polymorphism methods. Among the polymorphisms screened, 103 polymorphisms of 43 genes were included for further analyses. RESULTS: The genetic polymorphisms in the ABCC4, AHCY, ATIC, FAM8A6P, GART, GNG2, GSTA1, MTHFD1, MTHFR, NUDT15, PACSIN2, TYMS and XDH genes, and an intronic polymorphism between HIVEP2 and AIG1, and TPMT genotype were associated with thiopurine metabolism (P < 0.05). Genetic polymorphisms in the ABCC4, ADK, ATIC, GART, GMPS, GSTP1, IMPDH1, ITPA, KCNMA1, MOCOS, MTRR, NUDT15, SLC19A1, SLC28A3, SLC29A1, SLCO1B1, TYMP and XDH genes were associated with thiopurine-related toxicities; neutropenia, hepatotoxicity and treatment interruption (P < 0.05). CONCLUSIONS: Findings of this study may provide basic knowledge for personalized medicine for thiopurinxe treatment in paediatric acute lymphoblastic leukaemiapatients.
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