Whole exome sequencing based pharmacogenetic analysis in pediatric acute lymphoblastic leukemia
Whole exome sequencing based pharmacogenetic analysis in pediatric acute lymphoblastic leukemia
Abstract
Introduction: With the cure rate of childhood acute lymphoblastic leukemia (ALL) approaching 90%, further improvement will require optimizing treatment based on host and pharmacogenomics. In this study, whole exome sequencing based analysis was performed for pharmacogenetics analysis in Korean children with ALL. Methods: A total of 96 patients with ALL who received chemotherapy including maintenance phase at the Asan medical center were included. Whole exome sequencing was carried out with genomic DNA. Laboratory results and medication records were extracted from electrical medical records. Variants associated with specific phenotypes were analyzed. Results: The distribution of previously reported pharmacogenetic variants was NUDT15 rs116855232 (17.7%), ABCC4 rs2274407 (33.3%), ABCC4 rs3765534 (16.7%), ABCC4 rs11568658 (28.1%), SLCO1B1 rs11045879 (0%), SLCOB1 rs4149056 (19.8%), ITPA rs1127354 (21.9%), ITPA rs7270101 (0%), MTHFR rs1801131 (20.8%), MTHFR rs1801133 (71.9%), GRIA1 rs4958351 (0%), PACSIN2 rs2413739 (0%), BAG3 rs78439745 (10.4%) and TPMT (* 1 / * 3C and *6, 3.1%). The distribution of NUDT15 allele types were *1/*1 (N=76, 79.2%), *1/*2 (N=2, 2.1%), *1/*3 (N=15, 15.6%), *1/*4 (N=2, 2.1%), and *1/*5 (N=1, 1%). Grade 4 liver enzyme elevation was observed in 14 patients (14.6%) during treatment, and variant T allele in ABCC4 rs2274407 was associated with higher frequency of grade 4 liver enzyme elevation ( P=0.029). Comparing the average doses of MP used during maintenance phases, the T allele type of NUDT15 rs116855232 was significantly associated with a lower tolerated dose of MP as 67.9 and 54.1% of initially planned doses for CC and CT genotypes ( P=0.024). The cumulative incidence of neutropenia during maintenance was significantly higher in patients with variant forms of ABCC4 rs11568658, NUDT15 rs116855232 and TPMT; ABCC4 rs11568658 (CC:CA:AA=62%:63.6%:100%, P0.001), NUDT15 rs116855232 (CC:CT=59.4%:80%, P=0.007), and TPMT (*1/1: *1/3C: *1/6=62.6%:100%:100%, P=0.044). Conclusion: This study revealed that the variants in ABCC4 rs2274407 were associated with liver toxicity during treatment, and the variants in ABCC4 rs11568658, NUDT15 and TPMT were associated with MP related neutropenia in ALL. We expect more extensive researches about pharmacogenetics of Korean will be conducted in the future.