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 (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.

Figure 1. Distributions of summary statistics for A) the sensory subscale (eight items), and B) the motor items (eight items)

Outset: Following the conversion of the Likert “none”-“very much” scale to a 0–3 numeric scale, each individual was attributed a summary statistic for the sensory subscale (Cronbach α = 0.88) and the motor subscale (α = 0.78) by taking the mean of the responses in the subscale: none (0; mean = 0), a little (1; 0 < mean ≤ 1), quite a bit (2; 1 < mean ≤ 2), very much (3; 2 < mean ≤ 3). Inset: Percent of patients in each group (top of column lists actual number of patients) with groups 2 and 3 combined due to low frequency.

Figure 2. Relationship between weight gain and self-reported health, and severity of CisIPN

Barplots of CisIPN vs A. Weight gain (measured as the BMI difference between evaluation and therapy) and B. Self-reported health. BMI difference positively correlated with CisIPN (OR = 1.05) after adjusting for age (p = 0.009) or number of years since treatment (p = 0.004). Self-reported health (poor-excellent) strongly negatively correlated with CisIPN (OR = 0.56, p = 2.6 × 10⁻⁹), but not with age.

Figure 3. Genome-wide PrediXcan analysis of CisIPN in TCS

Manhattan and Q-Q plots of associations with PrediXcan expressions in 3 out of 4 candidate tissues tested, including A. GTEx skin – not exposed to sun, B. GTEx tibial nerve, C. DGN whole blood. Genes that passed the following criteria were included: prediction R² > 0.01, prediction p < 0.05, predicted expression variance > 0.001. Blue lines indicate significance threshold within the tissue, −log₁₀ (0.05/n_tissue) where n_tissue is the number of genes tested in the tissue. The green line indicates experiment-wide significance threshold, −log₁₀ (0.05/n_total) where n_total is the total number of tests performed.

Figure 4. Association of lower RPRD1B expression and CisIPN

Box and cumulative incidence plots of PrediXcan-predicted RPRD1B expression by neuropathy status reveal that lower expression correlates with neuropathy in A. The Platinum Study’s TCS cohort (p = 3.6 × 10⁻⁶), and B. Vanderbilt’s BioVU cohort (one tailed p = 0.021) and C. the CALGB 90401 docetaxel trial (one tailed p = 0.055). In plots A and B: The centers of the boxplots indicate means, the hinges indicate interquartile regions (IQR), the whiskers indicate points within 1.5 × IQR. Data beyond the end of the whiskers are outliers plotted as points. In plot B: Logistic regression was performed in BioVU to assess the association between PrediXcan expression and the code for polyneuropathy due to drugs – 1 for cases (n = 20), 0 for controls (n = 18,600). In plot C: Cox proportional hazards regression was performed to assess the association between PrediXcan expression and a dose-to-grade 3 or higher neuropathy event in the CALGB. An arbitrary cutoff is used to illustrate the association between the continuous gene expression variable and the dose-to-event phenotype: Individuals were ranked according to gene expression as determined by PrediXcan and the 1^st quartile refers to the 25% with the lowest genetically determined RPRD1B expression and 2^nd to 4^th refers to the remaining individuals. Replication was assessed by Fisher’s combined p-value of both replications (BioVu and CALGB) and met significance (p = 0.0089).