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

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 (TCS). 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 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’s 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.

Concomitant Medications and Risk of Chemotherapy-Induced Peripheral Neuropathy

“…Some of these drugs are related to peripheral neuropathy, such as statins or proton pump inhibitors, which are associated with vitamin B12 deficiency , a peripheral neuropathy risk factor. The number of concomitant medications could also be an indirect measurement of the general health status of the patients, which in cisplatin‐treated patients was found strongly associated with the neuropathy (OR, 0.59; p < .0001) .…”

Clinical and Genome-wide Analysis of Cisplatin-induced Tinnitus Implicates Novel Ototoxic Mechanisms

“…Genotyping was done as described previously (17,18). DNA was extracted from peripheral blood mononuclear cells.…”

“…QC for batch effects was performed using a batch pseudo-GWAS where variants associated with batch pseudo-phenotype (10 genotypic PC-adjusted P < 10 À4 ) were excluded. SNPs and samples passing QC criteria comprised the input set for imputation with EAGLE phasing, performed on the Michigan Imputation Server using the Haplotype Reference Consortium (18)(19)(20). SNPs with imputation R 2 < 0.8, MAF < 0.01, and INFO scores > 1.05 or < 0.3 were excluded.…”

Adverse Health Outcomes in Relationship to Hypogonadism After Chemotherapy: A Multicenter Study of Testicular Cancer Survivors

“…However, we previously showed that peripheral sensory neuropathy among TCS is associated with weight gain adjusted for years since treatment (P5.004). 40 Thus, it is possible that TCS with significant neuropathy may not be able to 9%); black/African American, 6 (1.2%); American Indian, 1 (0.2%); more than one race, 9 (1.8%); and declined to answer/other/ unknown, 40 (8.1%).…”