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Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy
- Source :
- Clinical cancer research : an official journal of the American Association for Cancer Research, vol 22, iss 19
- Publication Year :
- 2016
- Publisher :
- eScholarship, University of California, 2016.
-
Abstract
- Purpose: 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. 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: 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 × 10−8, adjusted P = 5.88 × 10−7). 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. Clin Cancer Res; 22(19); 4890–900. ©2016 AACR.
- Subjects :
- 0301 basic medicine
Male
Cancer Research
Genome-wide association study
Docetaxel
Bioinformatics
Inbred C57BL
Castration-Resistant
Prostate cancer
Mice
0302 clinical medicine
Antineoplastic Combined Chemotherapy Protocols
80 and over
Aged, 80 and over
Mice, Knockout
Intracellular Signaling Peptides and Proteins
Single Nucleotide
Middle Aged
Bevacizumab
Prostatic Neoplasms, Castration-Resistant
Oncology
Chemotherapy-induced peripheral neuropathy
030220 oncology & carcinogenesis
Taxoids
medicine.drug
Adult
Genotype
Knockout
Oncology and Carcinogenesis
Single-nucleotide polymorphism
and over
Polymorphism, Single Nucleotide
Article
03 medical and health sciences
Polyneuropathies
Double-Blind Method
medicine
SNP
Animals
Humans
Genetic Predisposition to Disease
Oncology & Carcinogenesis
Polymorphism
Aged
business.industry
Membrane Proteins
Prostatic Neoplasms
medicine.disease
Pharmacogenomic Testing
Mice, Inbred C57BL
030104 developmental biology
Prednisone
business
Pharmacogenetics
Genome-Wide Association Study
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research, vol 22, iss 19
- Accession number :
- edsair.doi.dedup.....5eba90052ddf87b386be592929c01ef6