Sensory peripheral neuropathy is a common and sometimes debilitating toxicity associated with paclitaxel therapy. This study aims to identify genetic risk factors for development of this toxicity

Baldwin, R. Michael

Chhibber, Aparna

Eclov, Rachel J.

Friedman, Paula N.

Hudis, Clifford A.

Jiang, Chen

Jorgenson, Eric M.

Kroetz, Deanna L.

Kubo, Michiaki

McLeod, Howard L.

Mefford, Joel

Nakamura, Yusuke

Owzar, Kouros

Ratain, Mark J.

Shulman, Lawrence N.

Watson, Dorothy

Winer, Eric P.

Witte, John S.

Zembutsu, Hitoshi

PubMed

Carolina Digital Repository

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

PurposeSensory 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 designA 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.ResultsA 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.ConclusionsA 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

Baldwin, R Michael

Eclov, Rachel J

McLeod, Howard L

Friedman, Paula N

Hudis, Clifford A

Winer, Eric P

Jorgenson, Eric M

Witte, John S

Shulman, Lawrence N

Ratain, Mark J

Kroetz, Deanna L

eScholarship - University of California

http://dx.doi.org/10.1158/1078-0432.CCR-12-1590

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

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