A Genome-Wide Association Study Identifies Novel Loci for Paclitaxel-Induced Sensory Peripheral Neuropathy in CALGB 40101

• Published in: Clinical cancer research Vol. 18; no. 18; pp. 5099 - 5109
• Main Authors: Baldwin, R. Michael, Owzar, Kouros, Zembutsu, Hitoshi, Chhibber, Aparna, Kubo, Michiaki, Jiang, Chen, Watson, Dorothy, Eclov, Rachel J., Mefford, Joel, McLeod, Howard L., Friedman, Paula N., Hudis, Clifford A., Winer, Eric P., Jorgenson, Eric M., Witte, John S., Shulman, Lawrence N., Nakamura, Yusuke, Ratain, Mark J., Kroetz, Deanna L.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.09.2012
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents, Phytogenic - adverse effects; Antineoplastic Agents, Phytogenic - therapeutic use; Biological and medical sciences; Breast Neoplasms - complications; Breast Neoplasms - drug therapy; Female; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Incidence; Medical sciences; Microfilament Proteins - genetics; Middle Aged; Paclitaxel - adverse effects; Paclitaxel - therapeutic use; Peripheral Nervous System Diseases - chemically induced; Peripheral Nervous System Diseases - genetics; Pharmacology. Drug treatments; Polymorphism, Single Nucleotide; Receptor, EphA5 - genetics; Sensory Receptor Cells - drug effects; Antineoplastic agent; Nervous system diseases; Taxane derivatives; Paclitaxel; A Genome; Peripheral nerve disease; Antimitotic
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-12-1590

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. Clin Cancer Res; 18(18); 5099–109. ©2012 AACR.