Genomewide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy.

TitleGenomewide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy.
Publication TypeJournal Article
Year of Publication2020
AuthorsChua, Katherina C., 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, and Deanna L. Kroetz
JournalClin Pharmacol Ther
Volume108
Issue3
Pagination625-634
Date Published2020 09
ISSN1532-6535
KeywordsAdult, Aged, Cells, Cultured, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Neurites, Paclitaxel, Peripheral Nervous System Diseases, Pharmacogenetics, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Randomized Controlled Trials as Topic, Risk Assessment, Risk Factors, Sphingosine-1-Phosphate Receptors, Tubulin Modulators, Young Adult
Abstract

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 ; e.g., rs74497159, β per allele log hazard ratio (95% confidence interval (CI)) = 0.591 (0.254-0.928), β per allele log hazard ratio (95% CI) = 0.693 (0.334-1.053); P  = 3.62 × 10 ) 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 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 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.

DOI10.1002/cpt.1958
Alternate JournalClin Pharmacol Ther
Original PublicationGenomewide meta-analysis validates a role for S1PR1 in microtubule targeting agent-induced sensory peripheral neuropathy.
PubMed ID32562552
PubMed Central IDPMC7718413
Grant ListUG1 CA233320 / CA / NCI NIH HHS / United States
R01 CA192156 / CA / NCI NIH HHS / United States
U10 CA180882 / CA / NCI NIH HHS / United States
P01 CA142538 / CA / NCI NIH HHS / United States
U10 CA180821 / CA / NCI NIH HHS / United States
U24 CA196171 / CA / NCI NIH HHS / United States
UG1 CA233327 / CA / NCI NIH HHS / United States
T32 GM007175 / GM / NIGMS NIH HHS / United States