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Hertz, Daniel L; Owzar, Kouros; Lessans, Sherrie; Wing, Claudia; Jiang, Chen; Kelly, William Kevin; Patel, Jai; Halabi, Susan; Furukawa, Yoichi; Wheeler, Heather E; Sibley, Alexander B; Lassiter, Cameron; Weisman, Lois; Watson, Dorothy; Krens, Stefanie D; Mulkey, Flora; Renn, Cynthia L; Small, Eric J; Febbo, Phillip G; Shterev, Ivo; Kroetz, Deanna L; Friedman, Paula N; Mahoney, John F; Carducci, Michael A; Kelley, Michael J; Nakamura, Yusuke; Kubo, Michiaki; Dorsey, Susan G; Dolan, M Eileen; Morris, Michael J; Ratain, Mark J; McLeod, Howard L
Clinical cancer research, 10/2016, Volume: 22, Issue: 19Journal Article
Discovery of SNPs that predict a patient's risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy. A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy. A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An SNP in VAC14 (rs875858) surpassed genome-wide significance (P = 2.12 × 10 , adjusted P = 5.88 × 10 ). siRNA knockdown of VAC14 in stem cell-derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (P = 0.0015) and branches (P < 0.0001). Prior to docetaxel treatment, VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (P = 0.001). VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890-900. ©2016 AACR.
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