基于新一代基因组测序和临床相关分析识别鉴定晚期视网膜母细胞瘤的个体化治疗的新靶点

Retinoblastoma is the most common pediatric retinal tumor initiated by biallelic inactivation of the retinoblastoma gene (RB1), the first identified tumor suppressor gene. The incidence rate of life-threatened retinoblastoma with invasiveness and metastasis has been increasing in China. The individual patients with high risk advanced retinoblastoma respond to chemotherapy vary widely. The challenge facing molecular biologists and clinical oncologists is to overcome adverse reactions and ressistance to chemotherapeutic agents for retinoblastoma, owing to genetic/epigenetic variations amonge individual patients. We hence propose to study pharmacogenomics for retinoblastoma, identifying and understanding genetic/epigenetic biomarkers with regarding to the prediction of outcome of chemotherapy treatment by using next-generation sequencing technology for whole-genome DNA resequencing, as well as mRNA expression profile and CpG methylation sites across the entire genome. Following with validation studies both clinically and experimentally, functional characterization will be further performed for mechanism of action of candidate genes. Firstly, It would help clinicians tailor personalized medicine to maximize drug effect and avoid drug toxicity, improving treatment outcomes of antineoplastic reagents. Secondly, it would provide insights of RB pathophysiological knowledge and action mechanism of drug resistance for retinoblastoma targeted treatment decisions.

视网膜母细胞瘤（Retinpblastoma, RB）是婴幼儿恶性肿瘤最常见的一种，由RB1抑癌基因功能丧失而引发。常伴有侵袭转移的晚期高风险RB在我国的发病率增多，严重威胁生命。国际首选方案为全身化疗辅以眼局部治疗，多因毒副作用或耐药而致临床疗效受限。目前对于RB患者个体间的基因多态性影响产生不同药物反应的研究尚不多见。本课题将应用药物基因组学，根据病侧眼球摘除术后经化疗的晚期RB患者复发转移情况，选取晚期RB组织样本，在国内首次采用新一代基因组DNA测序，结合mRNA表达和甲基化位点等芯片数据整合分析，识别药物反应相关的生物标志物和靶基因，以临床相关分析和实验加以验证，进而探讨功能机制，得以1）识别新的预测RB疗效的生物标志物，有助于最大限度地提高药物疗效和降低毒副作用，指导临床合理用药，达到RB个体化治疗；2）鉴定治疗新靶点，加深对RB药物耐药及病理机制的认识，提供靶向治疗的新思路。

视网膜母细胞瘤（Retinpblastoma, RB）是婴幼儿恶性肿瘤最常见的一种，由RB1抑癌基因功能丧失而引发。常伴有侵袭转移的晚期高风险RB在我国的发病率增多，严重威胁生命。国际首选方案为全身化疗辅以眼局部治疗，多因毒副作用或耐药而致临床疗效受限。目前对于RB患者个体间的基因多态性影响产生不同药物反应的研究尚不多见。本课题将应用药物基因组学，根据病侧眼球摘除术后经化疗的晚期RB患者复发转移情况，选取晚期RB组织样本，在国内首次采用新一代基因组DNA测序，结合mRNA表达和甲基化位点等芯片数据整合分析，识别药物反应相关的生物标志物和靶基因，以临床相关分析和实验加以验证，进而探讨功能机制，得以1）识别新的预测RB疗效的生物标志物，有助于最大限度地提高药物疗效和降低毒副作用，指导临床合理用药，达到RB个体化治疗；2）鉴定治疗新靶点，加深对RB药物耐药及病理机制的认识，提供靶向治疗的新思路。

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