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Clin Cancer Res. 2016 Oct 1;22(19):4890-4900. Epub 2016 May 3.

Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy.

Author information

1
Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan. UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
2
Duke Cancer Institute, Durham, North Carolina. Alliance Statistics and Data Center, Duke University, Durham, North Carolina.
3
Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore, Maryland.
4
Department of Medicine, University of Chicago, Chicago, Illinois.
5
Alliance Statistics and Data Center, Duke University, Durham, North Carolina.
6
Thomas Jefferson University, Philadelphia, Pennsylvania.
7
UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina.
8
Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
9
Duke Cancer Institute, Durham, North Carolina.
10
Life Sciences Institute, University of Michigan, Ann Arbor, Michigan.
11
UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht, the Netherlands.
12
Department of Medicine, UCSF, San Francisco, California.
13
Genomic Health, Redwood City, California.
14
Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
15
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California.
16
Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina.
17
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland.
18
Durham VA Medical Center, Duke University Medical Center, Durham, North Carolina.
19
Department of Medicine, University of Chicago, Chicago, Illinois. Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
20
Lab for Genotyping Development, Riken Center for Integrative Medical Sciences, Kanagawa, Japan.
21
Memorial Sloan Kettering Cancer Center, New York.
22
UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Personalized Medicine Institute, Moffitt Cancer Center, Tampa, Florida. Howard.mcleod@moffitt.org.

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.

PMID:
27143689
PMCID:
PMC5050068
DOI:
10.1158/1078-0432.CCR-15-2823
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare the following relevant conflicts of interest.

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