Polymorphisms of the vincristine pathway and response to treatment in children with childhood acute lymphoblastic leukemia. (June 2014)

• Record Type: Journal Article
• Authors: Ceppi, Francesco; Langlois-Pelletier, Chloé; Gagné, Vincent; Rousseau, Julie; Ciolino, Claire; Lorenzo, Samanta De; Kevin, Kojok M; Cijov, Diana; Sallan, Stephen E; Silverman, Lewis B; Neuberg, Donna; Kutok, Jeffery L; Sinnett, Daniel; Laverdière, Caroline; Krajinovic, Maja
• Is Part Of: Pharmacogenomics. Volume 15:Number 8(2014)
• Page Start: 1105
• Page End: 1116
• Publication Date: 2014-06
• Subjects: childhood leukemia -- peripheral neurotoxicity -- pharmacogenetics -- polymorphisms -- treatment outcome -- vincristine; Pharmacogenomics -- Periodicals; 615.1
• DOI: 10.2217/pgs.14.68
• Languages: English
• ISSNs: 1462-2416

Abstract

Background: Vincristine (VCR) is a standard component in the treatment of childhood acute lymphoblastic leukemia (ALL). VCR cytotoxicity is primarily due to its ability to disrupt the formation of microtubules of the mitotic spindle.Patients & methods: Seventeen polymorphisms in regulatory and coding regions of genes controlling VCR targets ( TUBB1, MAP4, ACTG1 and CAPG ) or potentially influencing VCR levels ( ABCB1 and CYP3A5 ) were investigated for an association with peripheral neuropathy and outcome in childhood ALL patients.Results: High-grade neurotoxicity was more frequent in carriers of the A allele of synonymous (Ala310) G to A (rs1135989) variation in the ACTG1 gene. Substitution (rs4728709) in the promoter of the ABCB1 gene had a protective effect against lower grade neurotoxicity and C to A variation (rs3770102) located 17 nucleotides upstream from the transcription start site had a protective effect against high-grade neurotoxicity. Patients with the ABCB1 3435TT genotype had lower event-free survival; the association with event-free survival was not supported by the analysis in the replication patient set.Conclusion: The polymorphisms in the ACTG1, CAPG and ABCB1 genes may modulate VCR-related neurotoxicity, whereas the risk of relapse seems not to be affected by the genes of the VCR pathway. Original submitted 19 June 2013; Revision submitted 31 March 2014