Department of Pediatrics and Adolescent Medicine and.
Department of Hematology, University Hospital Rigshospitalet, Copenhagen, Denmark.
Blood. 2020 Sep 3;136(10):1161-1168. doi: 10.1182/blood.2020005064.
Methotrexate (MTX) during maintenance therapy is essential for curing acute lymphoblastic leukemia (ALL), but dosing strategies aiming at adequate treatment intensity are challenged by interindividual differences in drug disposition. To evaluate genetic factors associated with MTX metabolism, we performed a genome-wide association study in 447 ALL cases from the Nordic Society for Pediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic single-nucleotide polymorphism rs1382539, located in a regulatory element of DHFR, was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 × 10-8) related to suppression of enhancer activity, whereas rs35789560 in FPGS (p.R466C, P = 5.6 × 10-9) was associated with decreased levels of long-chain MTX polyglutamates through reduced catalytic activity. Furthermore, the FPGS variant was linked with increased relapse risk (P = .044). These findings show a genetic basis for interpatient variability in MTX response and could be used to improve future dosing algorithms.
甲氨蝶呤（MTX）在维持治疗中对于治愈急性淋巴细胞白血病（ALL）至关重要，但由于药物处置的个体差异，旨在达到足够治疗强度的剂量策略受到了挑战。为了评估与 MTX 代谢相关的遗传因素，我们在北欧儿科血液学和肿瘤学会 ALL2008 研究中的 447 例 ALL 病例中进行了全基因组关联研究，并在一个独立的 196 例患者中验证了结果。位于 DHFR 调节元件中的基因间单核苷酸多态性 rs1382539 与短链 MTX 多聚谷氨酸水平升高相关（P=1.1×10-8），这与增强子活性抑制有关，而 FPGS 中的 rs35789560（p.R466C，P=5.6×10-9）与长链 MTX 多聚谷氨酸水平降低有关，这是由于催化活性降低所致。此外，FPGS 变异与复发风险增加相关（P=0.044）。这些发现表明了 MTX 反应个体间变异性的遗传基础，并可用于改进未来的剂量算法。
