期刊
CLINICAL CANCER RESEARCH
卷 23, 期 19, 页码 5757-5768出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-16-3224
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资金
- NIH, NCI [1 R01 CA157823]
- Pharmacogenomics Research Network (PGRN)-RIKEN Global Alliance [GM115370]
- Riken Center for Integrative Medical Science, Japan
- University of Chicago Cancer Research Foundation Women's Board
- GTEx [R01 MH090937]
- Conte Center for Neuropsychiatric Genomics [P50 MH094267]
- Office of the Director of the National Institutes of Health
- NCI
- NHGRI
- NHLBI
- NIDA
- NIMH
- NINDS
- NCI\SAIC-Frederick, Inc. (SAIC-F) [10XS170, 10XS171, X10S172]
- Laboratory, Data Analysis, and Coordinating Center (LDACC) [HHSN268201000029C]
- SAIC-F [10ST1035]
- University of Miami [DA006227, DA033684, N01MH000028]
- Statistical Methods development grants [MH090941, MH101814]
- University of Chicago [MH090951, MH090937, MH101820, MH101825]
- University of North Carolina-Chapel Hill [MH090936, MH101819]
- Harvard University [MH090948]
- Stanford University [MH101782]
- Washington University St Louis [MH101810]
- University of Pennsylvania [MH101822]
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 x 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 x 10(-9)) and weight gain adjusted for years since treatment (OR per Dkg/m(2), 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 x 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. (C) 2017 AACR.
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