title: Integration of cell line and clinical trial genome-wide analyses supports a polygenic architecture of Paclitaxel-induced sensory peripheral neuropathy.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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.
authors.affiliation: Sections of Hematology/Oncology and Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Heather E
authors.initials: HE
authors.lastname: Wheeler
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gamazon
authors.forename: Claudia
authors.initials: C
authors.lastname: Wing
authors.forename: Uchenna O
authors.initials: UO
authors.lastname: Njiaju
authors.forename: Chidiamara
authors.initials: C
authors.lastname: Njoku
authors.forename: Robert Michael
authors.initials: RM
authors.lastname: Baldwin
authors.forename: Kouros
authors.initials: K
authors.lastname: Owzar
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
authors.forename: Dorothy
authors.initials: D
authors.lastname: Watson
authors.forename: Ivo
authors.initials: I
authors.lastname: Shterev
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Zembutsu
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Hudis
authors.forename: Lawrence N
authors.initials: LN
authors.lastname: Shulman
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Kroetz
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: Mary Eileen
authors.initials: ME
authors.lastname: Dolan
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000627:therapeutic use / Q000633:toxicity; D001943:Breast Neoplasms / Q000150:complications* / Q000188:drug therapy; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D017239:Paclitaxel / Q000009:adverse effects* / Q000627:therapeutic use / Q000633:toxicity; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; C101059:RFX2 protein, human; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D017239:Paclitaxel