Clinical and Genome-Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer

Clin Cancer Res. 2017 Oct 1;23(19):5757-5768. doi: 10.1158/1078-0432.CCR-16-3224. Epub 2017 Jun 13.

Abstract

Purpose: Our purpose was to characterize the clinical influences, genetic risk factors, and gene mechanisms contributing to persistent cisplatin-induced peripheral neuropathy (CisIPN) in testicular cancer survivors (TCSs).Experimental Design: TCS given cisplatin-based therapy completed the validated EORTC QLQ-CIPN20 questionnaire. An ordinal CisIPN phenotype was derived, and associations with age, smoking, excess drinking, hypertension, body mass index, diabetes, hypercholesterolemia, cumulative cisplatin dose, and self-reported health were examined for 680 TCS. Genotyping was performed on the Illumina HumanOmniExpressExome chip. Following quality control and imputation, 5.1 million SNPs in 680 genetically European TCS formed the input set. GWAS and PrediXcan were used to identify genetic variation and genetically determined gene expression traits, respectively, contributing to CisIPN. We evaluated two independent datasets for replication: Vanderbilt's electronic health database (BioVU) and the CALGB 90401 trial.Results: Eight sensory items formed a subscale with good internal consistency (Cronbach α = 0.88). Variables significantly associated with CisIPN included age at diagnosis (OR per year, 1.06; P = 2 × 10-9), smoking (OR, 1.54; P = 0.004), excess drinking (OR, 1.83; P = 0.007), and hypertension (OR, 1.61; P = 0.03). CisIPN was correlated with lower self-reported health (OR, 0.56; P = 2.6 × 10-9) and weight gain adjusted for years since treatment (OR per Δkg/m2, 1.05; P = 0.004). PrediXcan identified lower expressions of MIDN and RPRD1B, and higher THEM5 expression as associated with CisIPN (P value for each < 5 × 10-6) with replication of RPRD1B meeting significance criteria (Fisher combined P = 0.0089).Conclusions: CisIPN is associated with age, modifiable risk factors, and genetically determined expression level of RPRD1B Further study of implicated genes could elucidate the pathophysiologic underpinnings of CisIPN. Clin Cancer Res; 23(19); 5757-68. ©2017 AACR.

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Age of Onset
  • Aged
  • Cancer Survivors
  • Cell Cycle Proteins / genetics*
  • Cisplatin / administration & dosage
  • Cisplatin / adverse effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • Hypertension / complications
  • Hypertension / genetics
  • Hypertension / pathology
  • Male
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Peripheral Nervous System Diseases / chemically induced
  • Peripheral Nervous System Diseases / genetics
  • Peripheral Nervous System Diseases / pathology*
  • Polymorphism, Single Nucleotide / genetics
  • Risk Factors
  • Testicular Neoplasms / complications
  • Testicular Neoplasms / drug therapy*
  • Testicular Neoplasms / genetics
  • Testicular Neoplasms / pathology

Substances

  • CREPT protein, human
  • Cell Cycle Proteins
  • Neoplasm Proteins
  • Cisplatin