Dataset Information

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

ABSTRACT: 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.A GWAS of paclitaxel-induced cytotoxicity was conducted in 247 LCLs from the HapMap Project and compared with a GWAS of 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.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.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.

SUBMITTER: Wheeler HE

PROVIDER: S-EPMC3549006 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Wheeler Heather E HE Gamazon Eric R ER Wing Claudia C Njiaju Uchenna O UO Njoku Chidiamara C Baldwin Robert Michael RM Owzar Kouros K Jiang Chen C Watson Dorothy D Shterev Ivo I Kubo Michiaki M Zembutsu Hitoshi H Winer Eric P EP Hudis Clifford A CA Shulman Lawrence N LN Nakamura Yusuke Y Ratain Mark J MJ Kroetz Deanna L DL Cox Nancy J NJ Dolan Mary Eileen ME

Clinical cancer research : an official journal of the American Association for Cancer Research 20121130 2

<h4>Purpose</h4>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.<h4>Experimental design</h4>A GWAS of paclitaxel-induced cytotoxicity was conducted in 247 LCLs from the HapMap Project and compared with a GWAS of sensory peripheral neuropathy in patients with breast cancer (n = 855) treated wit ...[more]

PMID: 23204130

Similar Datasets

Project description:PurposeChemotherapy-induced peripheral neuropathy (CIPN) is the major treatment-limiting toxicity of paclitaxel, which predominantly presents as sensory symptoms, with motor symptoms in some patients. Differentiating CIPN into subtypes has been recommended to direct CIPN research. The objective of this study was to investigate whether sensory and motor CIPN are distinct subtypes with different predictive biomarkers in patients with breast cancer receiving paclitaxel.MethodsData were from a prospective cohort of 60 patients with breast cancer receiving up to 12 weekly infusions of 80 mg/m2 paclitaxel (NCT02338115). European Organisation for Research and Treatment of Cancer Quality of Life questionnaire CIPN20 was used to evaluate CIPN. Clusters of the time course of sensory (CIPNS), motor (CIPNM), and the difference between sensory and motor (CIPNS-CIPNM) were identified using k-means clustering on principal component scores. Predictive metabolomic biomarkers of maximum CIPNS and CIPNM were investigated using linear regressions adjusted for baseline CIPN, paclitaxel pharmacokinetics, and body mass index.ResultsMore sensory than motor CIPN was found (CIPNS change: mean = 10.8, ranged [-3.3, 52.1]; CIPNM change: mean = 3.5, range: [-7.5, 35.0]). Three groups were identified with No CIPN, Mixed CIPN, and Sensory-dominant CIPN (maximum CIPNS: mean = 12.7 vs. 40.9 vs. 74.3, p < 0.001; maximum CIPNM: mean = 5.4 vs. 25.5 vs. 36.1, p < 0.001; average CIPNS-CIPNM: mean = 2.8 vs. 5.8 vs. 24.9, p < 0.001). Biomarkers of motor CIPN were similar to previously identified biomarkers of sensory CIPN, including lower serum histidine (p = 0.029).ConclusionOur findings suggest that sensory and motor CIPN co-occur and may not have differentiating metabolic biomarkers. These findings need to be validated in larger cohorts of patients treated with paclitaxel and other neurotoxic agents to determine the optimal approach to predict, prevent, and treat CIPN and improve patients' outcomes.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets