• Wright Galen E B GEB Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. , Ursula Amstutz, Britt I Drögemöller, Joanne Shih, Shahrad R Rassekh, Michael R Hayden, Bruce C Carleton, Ross Colin J D CJD BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada. Facul, and Canadian Pharmacogenomics Network for Drug Safety Consortium.
• Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
• Clin. Pharmacol. Ther. 2019 Feb 1; 105 (2): 402-410.

AbstractVincristine 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 × 10-5 ; OR = 4.9), and SLC5A7 rs1013940 (P = 9.00 × 10-4 ; 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 × 10-4 ; 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.© 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

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