Clinical and genome-wide analysis of cisplatin-induced peripheral neuropathy in survivors of adult-onset cancer

M. Eileen Dolan, Omar El Charif, Heather E. Wheeler, Eric R. Gamazon, Shirin Ardeshir-Rouhani-fard, Patrick Monahan, Darren R. Feldman, Robert J. Hamilton, David J. Vaughn, Clair J. Beard, Chunkit Fung, Jeri Kim, Sophie D. Fossa, Daniel L. Hertz, Taisei Mushiroda, Michiaki Kubo, Lawrence H. Einhorn, Nancy J. Cox, Lois B. Travis

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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 a =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 Dkg/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.

元の言語English
ページ(範囲)5757-5768
ページ数12
ジャーナルClinical Cancer Research
23
発行部数19
DOI
出版物ステータスPublished - 01-10-2017

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Dolan, M. E., Charif, O. E., Wheeler, H. E., Gamazon, E. R., Ardeshir-Rouhani-fard, S., Monahan, P., Feldman, D. R., Hamilton, R. J., Vaughn, D. J., Beard, C. J., Fung, C., Kim, J., Fossa, S. D., Hertz, D. L., Mushiroda, T., Kubo, M., Einhorn, L. H., Cox, N. J., & Travis, L. B. (2017). Clinical and genome-wide analysis of cisplatin-induced peripheral neuropathy in survivors of adult-onset cancer. Clinical Cancer Research, 23(19), 5757-5768. https://doi.org/10.1158/1078-0432.CCR-16-3224