Integration of cell line and clinical trial genome-wide analyses supports a polygenic architecture of paclitaxel-induced sensory peripheral neuropathy

Heather E. Wheeler, Eric R. Gamazon, Claudia Wing, Uchenna O. Njiaju, Chidiamara Njoku, Robert Michael Baldwin, Kouros Owzar, Chen Jiang, Dorothy Watson, Ivo Shterev, Michiaki Kubo, Hitoshi Zembutsu, Eric P. Winer, Clifford A. Hudis, Lawrence N. Shulman, Yusuke Nakamura, Mark J. Ratain, Deanna L. Kroetz, Nancy J. Cox, Mary Eileen Dolan

研究成果: Article

38 引用 (Scopus)

抄録

Purpose: We sought to show the relevance of a lymphoblastoid cell line (LCL) model in the discovery of clinically relevant genetic variants affecting chemotherapeutic response by comparing LCL genome-wide association study (GWAS) results to clinical GWAS results. Experimental Design: A GWAS of paclitaxel-induced cytotoxicity was conducted in 247 LCLs from the HapMapProject and compared with aGWASof sensory peripheral neuropathy in patients with breast cancer (n = 855) treated with paclitaxel in the Cancer and Leukemia Group B (CALGB) 40101 trial. Significant enrichment was assessed by permutation resampling analysis. Results: We observed an enrichment of LCL cytotoxicity-associated single-nucleotide polymorphisms (SNP) in the sensory peripheral neuropathy-associated SNPs from the clinical trial with concordant allelic directions of effect (empirical P = 0.007). Of the 24 SNPs that overlap between the clinical trial (P < 0.05) and the preclinical cytotoxicity study (P < 0.001), 19 of them are expression quantitative trait loci (eQTL), which is a significant enrichment of this functional class (empirical P = 0.0447). One of these eQTLs is located in RFX2, which encodes a member of the DNA-binding regulatory factor X family. Decreased expression of this gene by siRNA resulted in increased sensitivity of Neuroscreen-1(NS-1; rat pheochromocytoma) cells to paclitaxel as measured by reduced neurite outgrowth and increased cytotoxicity, functionally validating the involvement of RFX2 in nerve cell response to paclitaxel. Conclusions: The enrichment results and functional example imply that cellular models of chemotherapeutic toxicity may capture components of the underlying polygenic architecture of related traits in patients.

元の言語English
ページ(範囲)491-499
ページ数9
ジャーナルClinical Cancer Research
19
発行部数2
DOI
出版物ステータスPublished - 15-01-2013

Fingerprint

Peripheral Nervous System Diseases
Paclitaxel
Genome-Wide Association Study
Clinical Trials
Genome
Single Nucleotide Polymorphism
Cell Line
Quantitative Trait Loci
Pheochromocytoma
Small Interfering RNA
Leukemia
Research Design
Breast Neoplasms
Gene Expression
Neurons
DNA
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

これを引用

Wheeler, Heather E. ; Gamazon, Eric R. ; Wing, Claudia ; Njiaju, Uchenna O. ; Njoku, Chidiamara ; Baldwin, Robert Michael ; Owzar, Kouros ; Jiang, Chen ; Watson, Dorothy ; Shterev, Ivo ; Kubo, Michiaki ; Zembutsu, Hitoshi ; Winer, Eric P. ; Hudis, Clifford A. ; Shulman, Lawrence N. ; Nakamura, Yusuke ; Ratain, Mark J. ; Kroetz, Deanna L. ; Cox, Nancy J. ; Dolan, Mary Eileen. / Integration of cell line and clinical trial genome-wide analyses supports a polygenic architecture of paclitaxel-induced sensory peripheral neuropathy. :: Clinical Cancer Research. 2013 ; 巻 19, 番号 2. pp. 491-499.
@article{b0f5244c26ee41f9a996930efcfa70d4,
title = "Integration of cell line and clinical trial genome-wide analyses supports a polygenic architecture of paclitaxel-induced sensory peripheral neuropathy",
abstract = "Purpose: We sought to show the relevance of a lymphoblastoid cell line (LCL) model in the discovery of clinically relevant genetic variants affecting chemotherapeutic response by comparing LCL genome-wide association study (GWAS) results to clinical GWAS results. Experimental Design: A GWAS of paclitaxel-induced cytotoxicity was conducted in 247 LCLs from the HapMapProject and compared with aGWASof sensory peripheral neuropathy in patients with breast cancer (n = 855) treated with paclitaxel in the Cancer and Leukemia Group B (CALGB) 40101 trial. Significant enrichment was assessed by permutation resampling analysis. Results: We observed an enrichment of LCL cytotoxicity-associated single-nucleotide polymorphisms (SNP) in the sensory peripheral neuropathy-associated SNPs from the clinical trial with concordant allelic directions of effect (empirical P = 0.007). Of the 24 SNPs that overlap between the clinical trial (P < 0.05) and the preclinical cytotoxicity study (P < 0.001), 19 of them are expression quantitative trait loci (eQTL), which is a significant enrichment of this functional class (empirical P = 0.0447). One of these eQTLs is located in RFX2, which encodes a member of the DNA-binding regulatory factor X family. Decreased expression of this gene by siRNA resulted in increased sensitivity of Neuroscreen-1(NS-1; rat pheochromocytoma) cells to paclitaxel as measured by reduced neurite outgrowth and increased cytotoxicity, functionally validating the involvement of RFX2 in nerve cell response to paclitaxel. Conclusions: The enrichment results and functional example imply that cellular models of chemotherapeutic toxicity may capture components of the underlying polygenic architecture of related traits in patients.",
author = "Wheeler, {Heather E.} and Gamazon, {Eric R.} and Claudia Wing and Njiaju, {Uchenna O.} and Chidiamara Njoku and Baldwin, {Robert Michael} and Kouros Owzar and Chen Jiang and Dorothy Watson and Ivo Shterev and Michiaki Kubo and Hitoshi Zembutsu and Winer, {Eric P.} and Hudis, {Clifford A.} and Shulman, {Lawrence N.} and Yusuke Nakamura and Ratain, {Mark J.} and Kroetz, {Deanna L.} and Cox, {Nancy J.} and Dolan, {Mary Eileen}",
year = "2013",
month = "1",
day = "15",
doi = "10.1158/1078-0432.CCR-12-2618",
language = "English",
volume = "19",
pages = "491--499",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "2",

}

Wheeler, HE, Gamazon, ER, Wing, C, Njiaju, UO, Njoku, C, Baldwin, RM, Owzar, K, Jiang, C, Watson, D, Shterev, I, Kubo, M, Zembutsu, H, Winer, EP, Hudis, CA, Shulman, LN, Nakamura, Y, Ratain, MJ, Kroetz, DL, Cox, NJ & Dolan, ME 2013, 'Integration of cell line and clinical trial genome-wide analyses supports a polygenic architecture of paclitaxel-induced sensory peripheral neuropathy', Clinical Cancer Research, 巻. 19, 番号 2, pp. 491-499. https://doi.org/10.1158/1078-0432.CCR-12-2618

Integration of cell line and clinical trial genome-wide analyses supports a polygenic architecture of paclitaxel-induced sensory peripheral neuropathy. / Wheeler, Heather E.; Gamazon, Eric R.; Wing, Claudia; Njiaju, Uchenna O.; Njoku, Chidiamara; Baldwin, Robert Michael; Owzar, Kouros; Jiang, Chen; Watson, Dorothy; Shterev, Ivo; Kubo, Michiaki; Zembutsu, Hitoshi; Winer, Eric P.; Hudis, Clifford A.; Shulman, Lawrence N.; Nakamura, Yusuke; Ratain, Mark J.; Kroetz, Deanna L.; Cox, Nancy J.; Dolan, Mary Eileen.

:: Clinical Cancer Research, 巻 19, 番号 2, 15.01.2013, p. 491-499.

研究成果: Article

TY - JOUR

T1 - Integration of cell line and clinical trial genome-wide analyses supports a polygenic architecture of paclitaxel-induced sensory peripheral neuropathy

AU - Wheeler, Heather E.

AU - Gamazon, Eric R.

AU - Wing, Claudia

AU - Njiaju, Uchenna O.

AU - Njoku, Chidiamara

AU - Baldwin, Robert Michael

AU - Owzar, Kouros

AU - Jiang, Chen

AU - Watson, Dorothy

AU - Shterev, Ivo

AU - Kubo, Michiaki

AU - Zembutsu, Hitoshi

AU - Winer, Eric P.

AU - Hudis, Clifford A.

AU - Shulman, Lawrence N.

AU - Nakamura, Yusuke

AU - Ratain, Mark J.

AU - Kroetz, Deanna L.

AU - Cox, Nancy J.

AU - Dolan, Mary Eileen

PY - 2013/1/15

Y1 - 2013/1/15

N2 - Purpose: We sought to show the relevance of a lymphoblastoid cell line (LCL) model in the discovery of clinically relevant genetic variants affecting chemotherapeutic response by comparing LCL genome-wide association study (GWAS) results to clinical GWAS results. Experimental Design: A GWAS of paclitaxel-induced cytotoxicity was conducted in 247 LCLs from the HapMapProject and compared with aGWASof sensory peripheral neuropathy in patients with breast cancer (n = 855) treated with paclitaxel in the Cancer and Leukemia Group B (CALGB) 40101 trial. Significant enrichment was assessed by permutation resampling analysis. Results: We observed an enrichment of LCL cytotoxicity-associated single-nucleotide polymorphisms (SNP) in the sensory peripheral neuropathy-associated SNPs from the clinical trial with concordant allelic directions of effect (empirical P = 0.007). Of the 24 SNPs that overlap between the clinical trial (P < 0.05) and the preclinical cytotoxicity study (P < 0.001), 19 of them are expression quantitative trait loci (eQTL), which is a significant enrichment of this functional class (empirical P = 0.0447). One of these eQTLs is located in RFX2, which encodes a member of the DNA-binding regulatory factor X family. Decreased expression of this gene by siRNA resulted in increased sensitivity of Neuroscreen-1(NS-1; rat pheochromocytoma) cells to paclitaxel as measured by reduced neurite outgrowth and increased cytotoxicity, functionally validating the involvement of RFX2 in nerve cell response to paclitaxel. Conclusions: The enrichment results and functional example imply that cellular models of chemotherapeutic toxicity may capture components of the underlying polygenic architecture of related traits in patients.

AB - Purpose: We sought to show the relevance of a lymphoblastoid cell line (LCL) model in the discovery of clinically relevant genetic variants affecting chemotherapeutic response by comparing LCL genome-wide association study (GWAS) results to clinical GWAS results. Experimental Design: A GWAS of paclitaxel-induced cytotoxicity was conducted in 247 LCLs from the HapMapProject and compared with aGWASof sensory peripheral neuropathy in patients with breast cancer (n = 855) treated with paclitaxel in the Cancer and Leukemia Group B (CALGB) 40101 trial. Significant enrichment was assessed by permutation resampling analysis. Results: We observed an enrichment of LCL cytotoxicity-associated single-nucleotide polymorphisms (SNP) in the sensory peripheral neuropathy-associated SNPs from the clinical trial with concordant allelic directions of effect (empirical P = 0.007). Of the 24 SNPs that overlap between the clinical trial (P < 0.05) and the preclinical cytotoxicity study (P < 0.001), 19 of them are expression quantitative trait loci (eQTL), which is a significant enrichment of this functional class (empirical P = 0.0447). One of these eQTLs is located in RFX2, which encodes a member of the DNA-binding regulatory factor X family. Decreased expression of this gene by siRNA resulted in increased sensitivity of Neuroscreen-1(NS-1; rat pheochromocytoma) cells to paclitaxel as measured by reduced neurite outgrowth and increased cytotoxicity, functionally validating the involvement of RFX2 in nerve cell response to paclitaxel. Conclusions: The enrichment results and functional example imply that cellular models of chemotherapeutic toxicity may capture components of the underlying polygenic architecture of related traits in patients.

UR - http://www.scopus.com/inward/record.url?scp=84872549256&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84872549256&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-12-2618

DO - 10.1158/1078-0432.CCR-12-2618

M3 - Article

C2 - 23204130

AN - SCOPUS:84872549256

VL - 19

SP - 491

EP - 499

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 2

ER -