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

描述(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诊断出来的，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。仅靠临床变量不能令人满意地预测患者的结果。目前迫切需要生物标记物来帮助患者进行个体化癌症治疗。在改善了对治疗结果的预测后，人们也非常希望新的治疗药物能为患者提供替代选择。该项目的目标是确定与microRNA(MiRNA)相关的种系遗传和循环生物标记物作为晚期NSCLC患者生存的预测因子。MiRNAs可以调节多达三分之一的人类基因，并在人类癌症发生中发挥重要作用。遗传变异主要以单核苷酸多态(SNPs)的形式存在，尤其是miRNA调节通路(miR-SNPs)中的SNPs，也会影响宿主和靶基因的表达和/或功能。我们建议对肺癌中miR-SNPs和循环miRNAs进行系统研究。这项建议建立在MD Anderson癌症中心的肺癌人口基础上，拥有全面的流行病学和临床数据和丰富的生物标本。有三个具体的目的：1)在miR-SNPs中寻找预测晚期非小细胞肺癌患者生存的新的种系遗传位点。我们将使用一个发现和验证设计，每个阶段包括1,200名接受铂类药物治疗的患者；2)确定循环中的miRNAs是生存的预测因素 在晚期NSCLC患者中，使用总共800个血浆样本的测试和验证集；以及3)确定已识别的表观遗传miR-SNP和循环miRNA生物标记物的潜在致病结构背景、生物学功能和分子机制。这是一个重要和创新的项目，融合了流行病学、遗传遗传学、循环生物标记物、生物学和机械学研究以及临床前治疗开发。

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.