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A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101.

Publication ,  Journal Article
Baldwin, RM; Owzar, K; Zembutsu, H; Chhibber, A; Kubo, M; Jiang, C; Watson, D; Eclov, RJ; Mefford, J; McLeod, HL; Friedman, PN; Hudis, CA ...
Published in: Clin Cancer Res
September 15, 2012

PURPOSE: 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. EXPERIMENTAL DESIGN: 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.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

September 15, 2012

Volume

18

Issue

18

Start / End Page

5099 / 5109

Location

United States

Related Subject Headings

  • Sensory Receptor Cells
  • Receptor, EphA5
  • Polymorphism, Single Nucleotide
  • Peripheral Nervous System Diseases
  • Paclitaxel
  • Oncology & Carcinogenesis
  • Middle Aged
  • Microfilament Proteins
  • Incidence
  • Humans
 

Citation

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Baldwin, R. M., Owzar, K., Zembutsu, H., Chhibber, A., Kubo, M., Jiang, C., … Kroetz, D. L. (2012). A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101. Clin Cancer Res, 18(18), 5099–5109. https://doi.org/10.1158/1078-0432.CCR-12-1590
Baldwin, R Michael, Kouros Owzar, Hitoshi Zembutsu, Aparna Chhibber, Michiaki Kubo, Chen Jiang, Dorothy Watson, et al. “A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101.Clin Cancer Res 18, no. 18 (September 15, 2012): 5099–5109. https://doi.org/10.1158/1078-0432.CCR-12-1590.
Baldwin RM, Owzar K, Zembutsu H, Chhibber A, Kubo M, Jiang C, et al. A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101. Clin Cancer Res. 2012 Sep 15;18(18):5099–109.
Baldwin, R. Michael, et al. “A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101.Clin Cancer Res, vol. 18, no. 18, Sept. 2012, pp. 5099–109. Pubmed, doi:10.1158/1078-0432.CCR-12-1590.
Baldwin RM, Owzar K, Zembutsu H, Chhibber A, Kubo M, Jiang C, Watson D, Eclov RJ, Mefford J, McLeod HL, Friedman PN, Hudis CA, Winer EP, Jorgenson EM, Witte JS, Shulman LN, Nakamura Y, Ratain MJ, Kroetz DL. A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101. Clin Cancer Res. 2012 Sep 15;18(18):5099–5109.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

September 15, 2012

Volume

18

Issue

18

Start / End Page

5099 / 5109

Location

United States

Related Subject Headings

  • Sensory Receptor Cells
  • Receptor, EphA5
  • Polymorphism, Single Nucleotide
  • Peripheral Nervous System Diseases
  • Paclitaxel
  • Oncology & Carcinogenesis
  • Middle Aged
  • Microfilament Proteins
  • Incidence
  • Humans