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Medline ® Abstract for Reference 13

of 'Overview of neurologic complications of non-platinum cancer chemotherapy'

Cumulative genetic risk predicts platinum/taxane-induced neurotoxicity.
McWhinney-Glass S, Winham SJ, Hertz DL, Yen Revollo J, Paul J, He Y, Brown R, Motsinger-Reif AA, McLeod HL, Scottish Gynaecological Clinical Trials Group
Clin Cancer Res. 2013;19(20):5769. Epub 2013 Aug 20.
PURPOSE: The combination of a platinum and taxane are standard of care for many cancers, but the utility is often limited due to debilitating neurotoxicity. We examined whether single-nucleotide polymorphisms (SNP) from annotated candidate genes will identify genetic risk for chemotherapy-induced neurotoxicity.
PATIENTS AND METHODS: A candidate-gene association study was conducted to validate the relevance of 1,261 SNPs within 60 candidate genes in 404 ovarian cancer patients receiving platinum/taxane chemotherapy on the SCOTROC1 trial. Statistically significant variants were then assessed for replication in a separate 404 patient replication cohort from SCOTROC1.
RESULTS: Significant associations with chemotherapy-induced neurotoxicity were identified and replicated for four SNPs in SOX10, BCL2, OPRM1, and TRPV1. The population attributable risk for each of the four SNPs ranged from 5% to 35%, with a cumulative risk of 62%. According to the multiplicative model, the odds of developing neurotoxicity increase by a factor of 1.64 for every risk genotype. Patients possessing three risk variants have an estimated OR of 4.49 (2.36-8.54) compared to individuals with 0 risk variants. Neither the four SNPs nor the risk score were associated with progression-free survival or overall survival.
CONCLUSIONS: This study shows that SNPs in four genes have a significant cumulative association with increased risk for the development of chemotherapy-induced neurotoxicity, independent of patient survival.
Authors' Affiliations: Schools of Pharmacy and Medicine; Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill; Bioinformatics Research Center and Department of Statistics, North Carolina State University; The Beatson Oncology Centre, University of Glasgow, Glasgow; and Department of Oncology, Imperial College London, London, United Kingdom.