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

R. Michael Baldwin, Kouros Owzar, Hitoshi Zembutsu, Aparna Chhibber, Michiaki Kubo, Chen Jiang, Dorothy Watson, Rachel J. Eclov, Joel Mefford, Howard L. McLeod, Paula N. Friedman, Clifford A. Hudis, Eric P. Winer, Eric M. Jorgenson, John S. Witte, Lawrence N. Shulman, Yusuke Nakamura, Mark J. Ratain, Deanna L. Kroetz

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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; -3) replication cohort. There is also evidence that markers in additional 95% CI, 1.13-3.28; P = 6.7 - 10 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 paclitaxelinduced 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.

元の言語English
ページ(範囲)5099-5109
ページ数11
ジャーナルClinical Cancer Research
18
発行部数18
DOI
出版物ステータスPublished - 15-09-2012

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Baldwin, R. M., Owzar, K., Zembutsu, H., Chhibber, A., Kubo, M., Jiang, C., Watson, D., Eclov, R. J., Mefford, J., McLeod, H. L., Friedman, P. N., Hudis, C. A., Winer, E. P., Jorgenson, E. M., Witte, J. S., Shulman, L. N., Nakamura, Y., Ratain, M. J., & Kroetz, D. L. (2012). A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101. Clinical Cancer Research, 18(18), 5099-5109. https://doi.org/10.1158/1078-0432.CCR-12-1590