Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance).
A Chhibber, J Mefford, E A Stahl, S A Pendergrass, R M Baldwin, K Owzar, M Li, E P Winer, C A Hudis, H Zembutsu, M Kubo, Y Nakamura, H L McLeod, M J Ratain, L N Shulman, M D Ritchie, R M Plenge, J S Witte, D L Kroetz
Author Information
A Chhibber: 1] Departments of Bioengineering and Therapeutic Sciences, University of California at San Francisco, San Francisco, CA, USA [2] Institute for Human Genetics, University of California at San Francisco, San Francisco, CA, USA.
J Mefford: 1] Institute for Human Genetics, University of California at San Francisco, San Francisco, CA, USA [2] Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA, USA.
E A Stahl: 1] Division of Rheumatology, Immunology, and Allergy, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Medical and Population Genetics Program, Chemical Biology Program, Broad Institute, Cambridge, MA, USA.
S A Pendergrass: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, Eberly College of Science, The Huck Institutes of the Life Sciences, University Park, PA, USA.
R M Baldwin: 1] Departments of Bioengineering and Therapeutic Sciences, University of California at San Francisco, San Francisco, CA, USA [2] Institute for Human Genetics, University of California at San Francisco, San Francisco, CA, USA.
K Owzar: Alliance Statistics and Data Center, Duke University Medical Center, Durham, NC, USA.
M Li: 1] Departments of Bioengineering and Therapeutic Sciences, University of California at San Francisco, San Francisco, CA, USA [2] Institute for Human Genetics, University of California at San Francisco, San Francisco, CA, USA.
E P Winer: Dana-Farber Cancer Institute, Boston, MA, USA.
C A Hudis: Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
H Zembutsu: Laboratory of Molecular Medicine, University of Tokyo, Tokyo, Japan.
M Kubo: Center for Integrative Medical Sciences, Riken Center, Yokohama, Japan.
Y Nakamura: 1] Laboratory of Molecular Medicine, University of Tokyo, Tokyo, Japan [2] Center for Integrative Medical Sciences, Riken Center, Yokohama, Japan [3] Department of Medicine, University of Chicago, Chicago, IL, USA.
H L McLeod: Department of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
M J Ratain: Department of Medicine, University of Chicago, Chicago, IL, USA.
L N Shulman: Dana-Farber Cancer Institute, Boston, MA, USA.
M D Ritchie: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, Eberly College of Science, The Huck Institutes of the Life Sciences, University Park, PA, USA.
R M Plenge: 1] Division of Rheumatology, Immunology, and Allergy, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Medical and Population Genetics Program, Chemical Biology Program, Broad Institute, Cambridge, MA, USA.
J S Witte: 1] Institute for Human Genetics, University of California at San Francisco, San Francisco, CA, USA [2] Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA, USA.
D L Kroetz: 1] Departments of Bioengineering and Therapeutic Sciences, University of California at San Francisco, San Francisco, CA, USA [2] Institute for Human Genetics, University of California at San Francisco, San Francisco, CA, USA.
Peripheral neuropathy is a common dose-limiting toxicity for patients treated with paclitaxel. For most individuals, there are no known risk factors that predispose patients to the adverse event, and pathogenesis for paclitaxel-induced peripheral neuropathy is unknown. Determining whether there is a heritable component to paclitaxel-induced peripheral neuropathy would be valuable in guiding clinical decisions and may provide insight into treatment of and mechanisms for the toxicity. Using genotype and patient information from the paclitaxel arm of CALGB 40101 (Alliance), a phase III clinical trial evaluating adjuvant therapies for breast cancer in women, we estimated the variance in maximum grade and dose at first instance of sensory peripheral neuropathy. Our results suggest that paclitaxel-induced neuropathy has a heritable component, driven in part by genes involved in axon outgrowth. Disruption of axon outgrowth may be one of the mechanisms by which paclitaxel treatment results in sensory peripheral neuropathy in susceptible patients.
