Purpose: Discovery of single nucleotide polymorphisms (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. Experimental Design: 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. Results: 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. A SNP in VAC14 (rs875858) surpassed genome-wide significance (p=2.12x10-8 adjusted p=5.88x10-7). 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). Conclusions: VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization.
- Received November 19, 2015.
- Revision received March 11, 2016.
- Accepted April 4, 2016.
- Copyright ©2016, American Association for Cancer Research.