title: A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101.
abstract: OBJECTIVE
  Sensory peripheral neuropathy is a common and sometimes debilitating toxicity associated with paclitaxel therapy. This study aims to identify genetic risk factors for the development of this toxicity.
  
  
  METHODS
  A prospective pharmacogenetic analysis of patients with primary breast cancer, randomized to the paclitaxel arm of CALGB 40101, was used to identify genetic predictors of the onset and severity of sensory peripheral neuropathy. A genome-wide association study in 855 subjects of European ancestry was conducted and findings were replicated in additional European (n = 154) and African American (n = 117) subjects.
  
  
  RESULTS
  A single nucleotide polymorphism in FGD4 was associated with the onset of sensory peripheral neuropathy in the discovery cohort [rs10771973; HR, 1.57; 95% confidence interval (CI), 1.30-1.91; P = 2.6 × 10(-6)] and in a European (HR, 1.72; 95% CI, 1.06-2.80; P = 0.013) and African American (HR, 1.93; 95% CI, 1.13-3.28; P = 6.7 × 10(-3)) replication cohort. There is also evidence that markers in additional genes, including EPHA5 (rs7349683) and FZD3 (rs10771973), were associated with the onset or severity of paclitaxel-induced sensory peripheral neuropathy.
  
  
  CONCLUSIONS
  A genome-wide association study has identified novel genetic markers of paclitaxel-induced sensory peripheral neuropathy, including a common polymorphism in FGD4, a congenital peripheral neuropathy gene. These findings suggest that genetic variation may contribute to variation in development of this toxicity. Validation of these findings may allow for the identification of patients at increased risk of peripheral neuropathy and inform the use of an alternative to paclitaxel and/or the clinical management of this toxicity.
authors: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 1550 4th Street RH584E, San Francisco, CA 94158-2911, USA.
authors: R Michael
authors: RM
authors: Baldwin
authors: Kouros
authors: K
authors: Owzar
authors: Hitoshi
authors: H
authors: Zembutsu
authors: Aparna
authors: A
authors: Chhibber
authors: Michiaki
authors: M
authors: Kubo
authors: Chen
authors: C
authors: Jiang
authors: Dorothy
authors: D
authors: Watson
authors: Rachel J
authors: RJ
authors: Eclov
authors: Joel
authors: J
authors: Mefford
authors: Howard L
authors: HL
authors: McLeod
authors: Paula N
authors: PN
authors: Friedman
authors: Clifford A
authors: CA
authors: Hudis
authors: Eric P
authors: EP
authors: Winer
authors: Eric M
authors: EM
authors: Jorgenson
authors: John S
authors: JS
authors: Witte
authors: Lawrence N
authors: LN
authors: Shulman
authors: Yusuke
authors: Y
authors: Nakamura
authors: Mark J
authors: MJ
authors: Ratain
authors: Deanna L
authors: DL
authors: Kroetz
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000150:complications* / Q000188:drug therapy; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015994:Incidence; D008840:Microfilament Proteins / Q000235:genetics; D008875:Middle Aged; D017239:Paclitaxel / Q000009:adverse effects* / Q000627:therapeutic use; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D036123:Receptor, EphA5 / Q000235:genetics; D011984:Sensory Receptor Cells / Q000187:drug effects*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C485164:FGD4 protein, human; D008840:Microfilament Proteins; D036123:Receptor, EphA5; D017239:Paclitaxel