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

  • Author(s): 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
  • Cancer and Leukemia Group B
  • Cox, Nancy J
  • Dolan, Mary Eileen
  • et al.
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 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.

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