Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy Implicates Pharmacokinetic and Inherited Neuropathy Genes.

Wright, Galen E B; Amstutz, Ursula; Drögemöller, Britt I; Shih, Joanne; Rassekh, Shahrad R; Hayden, Michael R; Carleton, Bruce C; Ross, Colin J D (2019). Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy Implicates Pharmacokinetic and Inherited Neuropathy Genes. Clinical pharmacology and therapeutics, 105(2), pp. 402-410. Wiley 10.1002/cpt.1179

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry

UniBE Contributor:

Amstutz, Ursula

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1532-6535

Publisher:

Wiley

Language:

English

Submitter:

Marie-Christine Müller

Date Deposited:

08 Mar 2019 14:34

Last Modified:

25 Oct 2019 12:27

Publisher DOI:

10.1002/cpt.1179

PubMed ID:

29999516

BORIS DOI:

10.7892/boris.125806

URI:

https://boris.unibe.ch/id/eprint/125806

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