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Genome-Wide Meta-Analysis Identifies a S1PR1 Genomic Region Associated with Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy

By Katherina C. Chua, Chenling Xiong, Carol Ho, Taisei Mushiroda, Chen Jiang, Flora Mulkey, Dongbing Lai, Bryan P Schneider, Sara R Rashkin, John S. Witte, Paula N Friedman, Mark J Ratain, Howard L McLeod, Hope S Rugo, Lawrence N Shulman, Michiaki Kubo, Kouros Owzar, Deanna L Kroetz

Posted 30 Apr 2020
medRxiv DOI: 10.1101/2020.04.23.20076208

Microtubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genome-wide association studies (GWAS) from two clinical cohorts treated with MTAs (CALGB 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR1; e.g., rs74497159, {beta}CALGB 40101 per allele log hazard ratio (95% CI) = 0.591 (0.254 - 0.928), {beta}CALGB 40502 per allele log hazard ratio (95% CI) = 0.693 (0.334 - 1.053); PMETA = 3.62x10-7) were the most highly ranked associations based on P-values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in iPSC-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.

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