Genomewide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy.
Genomewide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy.
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DOI：
10.1002/cpt.1958
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发表时间：
2020-09
影响因子：
6.7
通讯作者：
Kroetz DL
中科院分区：
文献类型：
--
作者：
Chua KC;Xiong C;Ho C;Mushiroda T;Jiang C;Mulkey F;Lai D;Schneider BP;Rashkin SR;Witte JS;Friedman PN;Ratain MJ;McLeod HL;Rugo HS;Shulman LN;Kubo M;Owzar K;Kroetz DL
微管靶向剂（MTA）是通常用于乳腺癌和其他实体瘤的抗癌疗法。感觉性周围神经病变（PN）是MTA的主要剂量限制性毒性，并可限制临床疗效。当前的药物基因组学研究旨在确定解释患者易感性的遗传变异和MTA诱导PN发生的驱动机制。使用考克斯回归模型对接受MTA治疗的两个临床队列（CALGB 40502和CALGB 40101）的全基因组关联研究（GWAS）进行了荟萃分析，其中首次出现2级或更高PN的累积剂量。对来自CALGB 40502中估计PN病因特异性风险的欧洲受试者GWAS（n = 469）的汇总统计量与来自CALGB 40101中估计PN风险的既往发表的欧洲血统GWAS（n = 855）的汇总统计量进行荟萃分析。鞘氨醇-1-磷酸受体1（编码S1 PR 1的S1 PR 1;例如，rs74497159，βCALGB 40101/等位基因对数风险比（95% CI）= 0.591（0.254 - 0.928），βCALGB 40502/等位基因对数风险比（95% CI）= 0.693（0.334 - 1.053）; PMETA = 3.62×10−7）是基于P值的与发生2级和更高PN风险的最高等级关联。计算机功能分析确定了该基因组区域内S1 PR 1的多个调控元件和潜在的增强子活性。在iPSC衍生的人感觉神经元中抑制S1 PR 1功能显示出对紫杉醇诱导的神经突损伤的部分保护。这些药物遗传学发现进一步支持正在进行的临床评价，以靶向S1 PR 1作为预防和/或治疗MTA诱导的神经病变的治疗策略。NCT 00785291（CALGB 40502）和NCT 00041119（CALGB 40101）
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, 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. NCT00785291 (CALGB 40502) and NCT00041119 (CALGB 40101)
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DOI：
10.1158/1078-0432.ccr-15-0133
发表时间：
2015-10-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Komatsu M;Wheeler HE;Chung S;Low SK;Wing C;Delaney SM;Gorsic LK;Takahashi A;Kubo M;Kroetz DL;Zhang W;Nakamura Y;Dolan ME
通讯作者：
Dolan ME
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
DOI：
10.1073/pnas.1820466116
发表时间：
2019-05-21
影响因子：
11.1
作者：
Chen, Zhoumou;Doyle, Timothy M.;Salvemini, Daniela
通讯作者：
Salvemini, Daniela
影响因子：
7.4
作者：
Doolen S;Iannitti T;Donahue RR;Shaw BC;Grachen CM;Taylor BK
通讯作者：
Taylor BK