Author:
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.
Abstract
AbstractMicrotubule 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, βCALGB40101 per allele log hazard ratio (95% CI) = 0.591 (0.254 - 0.928), βCALGB40502 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.
Publisher
Cold Spring Harbor Laboratory
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
1. Preventive Strategies for Chemotherapy-Induced Peripheral Neuropathy;Diagnosis, Management and Emerging Strategies for Chemotherapy-Induced Neuropathy;2021
2. Predisposing Factors for the Development of Chemotherapy-Induced Peripheral Neuropathy (CIPN);Diagnosis, Management and Emerging Strategies for Chemotherapy-Induced Neuropathy;2021