Chua, Katherina C.Xiong, ChenlingHo, CarolMushiroda, TaiseiJiang, ChenMulkey, FloraLai, DongbingSchneider, Bryan P.Rashkin, Sara R.Witte, John S.Friedman, Paula N.Ratain, Mark J.McLeod, Howard L.Rugo, Hope S.Shulman, Lawrence N.Kubo, MichiakiOwzar, KourosKroetz, Deanna L.2023-03-132023-03-132020-09Chua KC, Xiong C, Ho C, et al. Genomewide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy. Clin Pharmacol Ther. 2020;108(3):625-634. doi:10.1002/cpt.1958https://hdl.handle.net/1805/31845Microtubule 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, βCALGB 40101 per allele log hazard ratio (95% CI) = 0.591 (0.254 – 0.928), βCALGB 40502 per allele log hazard ratio (95% CI) = 0.693 (0.334 – 1.053); PMETA = 3.62×10−7) 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.en-USPublisher PolicyChemotherapySensory peripheral neuropathyChemotherapy-induced peripheral neuropathyGenome-wide associationPharmacogeneticsS1PR1Article