Title | A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | R Baldwin, Michael, 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, and Deanna L. Kroetz |
Journal | Clin Cancer Res |
Volume | 18 |
Issue | 18 |
Pagination | 5099-109 |
Date Published | 2012 Sep 15 |
ISSN | 1557-3265 |
Keywords | Adult, Aged, Antineoplastic Agents, Phytogenic, Breast Neoplasms, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Incidence, Microfilament Proteins, Middle Aged, Paclitaxel, Peripheral Nervous System Diseases, Polymorphism, Single Nucleotide, Receptor, EphA5, Sensory Receptor Cells |
Abstract | 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. |
DOI | 10.1158/1078-0432.CCR-12-1590 |
Alternate Journal | Clin Cancer Res |
Original Publication | A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101. |
PubMed ID | 22843789 |
PubMed Central ID | PMC3445665 |
Grant List | CA33601 / CA / NCI NIH HHS / United States U01 GM061393 / GM / NIGMS NIH HHS / United States U10 CA031946 / CA / NCI NIH HHS / United States U10 CA033601 / CA / NCI NIH HHS / United States GM61390 / GM / NIGMS NIH HHS / United States GM61393 / GM / NIGMS NIH HHS / United States U01 GM061390 / GM / NIGMS NIH HHS / United States U19 GM061390 / GM / NIGMS NIH HHS / United States P01 CA142538 / CA / NCI NIH HHS / United States T32 GM007175 / GM / NIGMS NIH HHS / United States CA31946 / CA / NCI NIH HHS / United States |
A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101.
Project: