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Genomewide Meta‐Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent‐Induced Sensory Peripheral Neuropathy
Author(s) -
Chua Katherina C.,
Xiong Chenling,
Ho Carol,
Mushiroda Taisei,
Jiang Chen,
Mulkey Flora,
Lai Dongbing,
Schneider Bryan P.,
Rashkin Sara R.,
Witte John S.,
Friedman Paula N.,
Ratain Mark J.,
McLeod Howard L.,
Rugo Hope S.,
Shulman Lawrence N.,
Kubo Michiaki,
Owzar Kouros,
Kroetz Deanna L.
Publication year - 2020
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1958
Subject(s) - genome wide association study , oncology , hazard ratio , medicine , breast cancer , single nucleotide polymorphism , s1pr1 , biology , confidence interval , cancer , genetics , genotype , vascular endothelial growth factor a , vascular endothelial growth factor , gene , vegf receptors
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 genomewide association studies (GWAS) from two clinical cohorts treated with MTAs (Cancer and Leukemia Group B (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 S1PR 1 ; e.g., rs74497159, β CALGB 40101 per allele log hazard ratio (95% confidence interval (CI)) = 0.591 (0.254–0.928), β CALGB 40502 per allele log hazard ratio (95% CI) = 0.693 (0.334–1.053); P META = 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 S1PR 1 function in induced pluripotent stem cell‐derived human sensory neurons shows partial protection against paclitaxel‐induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR 1 as a therapeutic strategy for prevention and/or treatment of MTA‐induced neuropathy.