Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
Clin Pharmacol Ther. 2019 Feb;105(2):402-410. doi: 10.1002/cpt.1179. Epub 2018 Aug 17.
Vincristine is an effective chemotherapeutic drug for various cancers, including acute lymphoblastic leukemia (ALL). Unfortunately, clinical utility is restricted by dose-limiting vincristine-induced peripheral neuropathies (VIPN). We sought to determine the association of VIPN with a recently identified risk variant, CEP72 rs924607, and drug absorption, distribution, metabolism, and excretion (ADME) gene variants in pediatric ALL. This was followed by a meta-analysis of pharmacogenomic data from over 500 patients. CEP72 rs924607 was significantly associated with VIPN (P = 0.02; odds ratio (OR) = 3.4). ADME analyses identified associations between VIPN and ABCC1 rs3784867 (P = 5.34 × 10 ; OR = 4.9), and SLC5A7 rs1013940 (P = 9.00 × 10 ; OR= 8.6); genes involved in vincristine transport and inherited neuropathies, respectively. Meta-analysis identified an association with a variant related to TTPA (rs10504361: P = 6.85 × 10 ; OR = 2.0), a heritable neuropathy-related gene. This study provides essential corroboratory evidence for CEP72 rs924607 and highlights the importance of drug transporter and inherited neuropathy genes in VIPN.
长春新碱是一种有效的化疗药物，可用于多种癌症，包括急性淋巴细胞白血病（ALL）。不幸的是，由于剂量限制的长春新碱诱导的周围神经病变（VIPN），其临床应用受到限制。我们试图确定 VIPN 与最近发现的风险变异 CEP72 rs924607 以及儿科 ALL 中药物吸收、分布、代谢和排泄（ADME）基因变异之间的关联。随后对超过 500 名患者的药物基因组学数据进行了荟萃分析。CEP72 rs924607 与 VIPN 显著相关（P = 0.02；优势比（OR）= 3.4）。ADME 分析确定了 VIPN 与 ABCC1 rs3784867（P = 5.34×10；OR = 4.9）和 SLC5A7 rs1013940（P = 9.00×10；OR = 8.6）之间的关联；这两个基因分别参与长春新碱的转运和遗传性神经病。荟萃分析确定了与 TTPA（rs10504361：P = 6.85×10；OR = 2.0）相关的变异体与遗传性神经病相关基因之间存在关联。本研究为 CEP72 rs924607 提供了重要的佐证证据，并强调了药物转运蛋白和遗传性神经病基因在 VIPN 中的重要性。
