Epigenetic miRNA, SNP Signatures, and their Functions in Lung Cancer Outcomes

描述（由申请人提供）：非小细胞肺癌（NSCLC）占所有肺癌病例的80%以上。超过三分之二的非小细胞肺癌是在晚期被诊断出来的，而目前的治疗在很大程度上是无效的，只有一小部分患者受益。仅凭临床变量不能令人满意地预测患者的预后。迫切需要生物标志物来帮助患者分层进行个性化的癌症治疗。在改善治疗结果预测后，也非常需要新的治疗药物给患者提供替代选择。该项目的目标是确定与microRNA （miRNA）相关的生殖系遗传和循环生物标志物作为晚期NSCLC患者生存的预测因子。mirna可以调节多达三分之一的人类基因，并在人类致癌过程中发挥重要作用。这些遗传变异，主要以单核苷酸多态性（snp）的形式存在，尤其是miRNA调控途径中的snp (mir - snp)，也可以影响其宿主和靶基因的表达和/或功能。我们建议对肺癌中mir - snp和循环mirna进行系统研究。该建议建立在MD安德森癌症中心肺癌人群的基础上，具有全面的流行病学和临床数据以及丰富的生物标本。有三个具体目的：1)在预测晚期NSCLC患者生存的mir - snp中鉴定新的种系遗传位点。我们将采用发现和验证设计，每个阶段包括1200名接受铂治疗的患者；2)鉴定循环mirna作为生存预测因子

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) comprises over 80% of all lung cancer cases. More than two-thirds of NSCLC are diagnosed at a late stage, when current treatments are largely ineffective and only benefit a small portion of patients. Clinical variables alone cannot satisfactorily predict patients' outcomes. Biomarkers are urgently needed to assist in the patient stratification for personalized cancer therapy. Novel therapeutic agents are also highly desired to give patients alternative options after improved prediction of outcomes of treatments. The goals of this project are to identify germline genetic and circulating biomarkers related to microRNA (miRNA) as predictors of survival in late stage NSCLC patients. MiRNAs can regulate up to a third of human genes and play important roles in human carcinogenesis. The inherited genetic variants, mostly in the form of single nucleotide polymorphisms (SNPs), particularly SNPs in miRNA regulatory pathways (miR-SNPs), can also affect expression and/or function of their host and target genes. We propose to conduct a systematic study of miR-SNPs and circulating miRNAs in lung cancer. This proposal builds upon a lung cancer population at MD Anderson Cancer Center, with comprehensive epidemiological and clinical data and rich bio specimens. There are three specific aims: 1) to identify novel germline genetic loci in miR-SNPs that predict survival in patients with late-stage NSCLC. We will use a discovery and validation design with each phase consisting of 1,200 patients for platinum-treated patients; 2) to identify circulating miRNAs as predictors of survival in late- stage NSCLC patients using a testing and a validation set with a total of 800 plasma samples; and 3) to determine the potential disease-causative structural context, biological function, and molecular mechanism of the identified epigenetic miR-SNP and circulating miRNA biomarkers. This is a significant and innovative project incorporating epidemiology, inherited genetics, circulating biomarkers, biological and mechanistic studies, and preclinical therapeutic development.