title: Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: 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.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Hertz
authors.affiliation: Duke Cancer Institute, Durham, North Carolina. Alliance Statistics and Data Center, Duke University, Durham, North Carolina.
authors.forename: Kouros
authors.initials: K
authors.lastname: Owzar
authors.affiliation: Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore, Maryland.
authors.forename: Sherrie
authors.initials: S
authors.lastname: Lessans
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wing
authors.affiliation: Alliance Statistics and Data Center, Duke University, Durham, North Carolina.
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: William Kevin
authors.initials: WK
authors.lastname: Kelly
authors.affiliation: 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.
authors.forename: Jai
authors.initials: J
authors.lastname: Patel
authors.affiliation: Duke Cancer Institute, Durham, North Carolina. Alliance Statistics and Data Center, Duke University, Durham, North Carolina.
authors.forename: Susan
authors.initials: S
authors.lastname: Halabi
authors.affiliation: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Furukawa
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Heather E
authors.initials: HE
authors.lastname: Wheeler
authors.affiliation: Duke Cancer Institute, Durham, North Carolina.
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Sibley
authors.affiliation: Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore, Maryland.
authors.forename: Cameron
authors.initials: C
authors.lastname: Lassiter
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan.
authors.forename: Lois
authors.initials: L
authors.lastname: Weisman
authors.affiliation: Alliance Statistics and Data Center, Duke University, Durham, North Carolina.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Watson
authors.affiliation: 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.
authors.forename: Stefanie D
authors.initials: SD
authors.lastname: Krens
authors.affiliation: Alliance Statistics and Data Center, Duke University, Durham, North Carolina.
authors.forename: Flora
authors.initials: F
authors.lastname: Mulkey
authors.affiliation: Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore, Maryland.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Renn
authors.affiliation: Department of Medicine, UCSF, San Francisco, California.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Small
authors.affiliation: Genomic Health, Redwood City, California.
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Febbo
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
authors.forename: Ivo
authors.initials: I
authors.lastname: Shterev
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California.
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Kroetz
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Paula N
authors.initials: PN
authors.lastname: Friedman
authors.affiliation: Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina.
authors.forename: John F
authors.initials: JF
authors.lastname: Mahoney
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.affiliation: Durham VA Medical Center, Duke University Medical Center, Durham, North Carolina.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kelley
authors.affiliation: 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.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Lab for Genotyping Development, Riken Center for Integrative Medical Sciences, Kanagawa, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore, Maryland.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Dorsey
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morris
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.affiliation: 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.
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D000068258:Bevacizumab / Q000008:administration & dosage / Q000009:adverse effects; D000077143:Docetaxel; D004311:Double-Blind Method; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D000071185:Pharmacogenomic Testing; D020641:Polymorphism, Single Nucleotide; D011115:Polyneuropathies / Q000139:chemically induced* / Q000235:genetics; D011241:Prednisone / Q000008:administration & dosage / Q000009:adverse effects; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy*; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D043823:Taxoids; C494631:VAC14 protein, human; D000077143:Docetaxel; D000068258:Bevacizumab; D011241:Prednisone