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

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posted on 2023-03-31, 20:05 authored by 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

Supplementary Figures and Tables for Clinical and Genome Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer Figure S1. Diagram of Data Collection Pipeline. Table S1. EORTC-CIPN20 questionnaire. Figure S2. Flow diagram of GWAS Quality Control Pipeline. Table S2. Additional Diagnosis and Treatment Characteristics of TCS cohort. Figure S3. Response frequencies for the EORTC-CIPN20 questionnaire from 680 patients. Figure S4. Principal Component Analysis (PCA) of EORTC-CIPN20 items. Figure S5. SNP-level GWAS. Table S3. Top 100 GWAS Results (p < 2.25 x 10-5) Table S4. Review of candidate gene studies implicating SNPs in cisplatin-induced neuropathy and their replication in the TCS study. Table S5. Review of previous GWAS of CIPN implicating SNPs and their replication in the TCS study. Table S6. Top PrediXcan results (P < 0.001).

Funding

NIH

NCI

RIKEN Global Alliance

Riken Center for Integrative Medical Science, Japan, the University of Chicago Cancer Research Foundation Women's Board

GTEx Project

Conte Center for Neuropsychiatric Genomics

NHGRI

NHLBI

NIDA

NIMH

NINDS

National Disease Research Interchange

Roswell Park Cancer Institute

Science Care, Inc.

LDACC

Van Andel Institute

SAIC

University of Miami

University of Geneva

University of Chicago

University of North Carolina

Harvard University

Stanford University

Washington University St Louis

University of Pennsylvania

History

ARTICLE 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.

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