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

Research output: Contribution to journalArticle

109 Citations (Scopus)

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; -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.

Original languageEnglish
Pages (from-to)5099-5109
Number of pages11
JournalClinical Cancer Research
Volume18
Issue number18
DOIs
Publication statusPublished - 15-09-2012

Fingerprint

Genome-Wide Association Study
Peripheral Nervous System Diseases
Paclitaxel
Confidence Intervals
African Americans
Genetic Markers
Genes
Single Nucleotide Polymorphism
Research Design
Breast Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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. / A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 18. pp. 5099-5109.
@article{fa2cb33ad0c34a118e33e7db84eeea5e,
title = "A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101",
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; -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.",
author = "Baldwin, {R. Michael} and Kouros Owzar and Hitoshi Zembutsu and Aparna Chhibber and Michiaki Kubo and Chen Jiang and Dorothy Watson and Eclov, {Rachel J.} and Joel Mefford and McLeod, {Howard L.} and Friedman, {Paula N.} and Hudis, {Clifford A.} and Winer, {Eric P.} and Jorgenson, {Eric M.} and Witte, {John S.} and Shulman, {Lawrence N.} and Yusuke Nakamura and Ratain, {Mark J.} and Kroetz, {Deanna L.}",
year = "2012",
month = "9",
day = "15",
doi = "10.1158/1078-0432.CCR-12-1590",
language = "English",
volume = "18",
pages = "5099--5109",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "18",

}

Baldwin, RM, Owzar, K, Zembutsu, H, Chhibber, A, Kubo, M, Jiang, C, Watson, D, Eclov, RJ, Mefford, J, McLeod, HL, Friedman, PN, Hudis, CA, Winer, EP, Jorgenson, EM, Witte, JS, Shulman, LN, Nakamura, Y, Ratain, MJ & Kroetz, DL 2012, 'A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101', Clinical Cancer Research, vol. 18, no. 18, pp. 5099-5109. https://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. / 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.

In: Clinical Cancer Research, Vol. 18, No. 18, 15.09.2012, p. 5099-5109.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101

AU - Baldwin, R. Michael

AU - Owzar, Kouros

AU - Zembutsu, Hitoshi

AU - Chhibber, Aparna

AU - Kubo, Michiaki

AU - Jiang, Chen

AU - Watson, Dorothy

AU - Eclov, Rachel J.

AU - Mefford, Joel

AU - McLeod, Howard L.

AU - Friedman, Paula N.

AU - Hudis, Clifford A.

AU - Winer, Eric P.

AU - Jorgenson, Eric M.

AU - Witte, John S.

AU - Shulman, Lawrence N.

AU - Nakamura, Yusuke

AU - Ratain, Mark J.

AU - Kroetz, Deanna L.

PY - 2012/9/15

Y1 - 2012/9/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84866415102&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866415102&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-12-1590

DO - 10.1158/1078-0432.CCR-12-1590

M3 - Article

C2 - 22843789

AN - SCOPUS:84866415102

VL - 18

SP - 5099

EP - 5109

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 18

ER -