Integrated Molecular, Cellular, and Imaging Characterization of NLST detected lung cancer

项目总结/摘要 具有里程碑意义的NLST表明，在接受低剂量化疗的个体中，肺癌死亡率降低了20%。 剂量计算机断层扫描（LDCT）筛查相对于胸部平片。NLST的结果 已经导致了美国医疗政策的巨大变化，例如第三方支付者和医疗保险现在提供 LDCT筛查作为符合条件的高危吸烟者的预防性服务获益。了解因素 潜在的肿瘤惰性或侵略性，导致异质性的临床结果，可能有助于临床 在肺癌筛查的背景下做出决策，从而大大提高其有效性。我们 假设筛查检测到的肺癌的突变景观是其发生的重要因素， 懒惰或侵略性。为了解决这一假设，我们将全面利用 注释的NLST生物储存库。先前收集的NLST样本的全外显子组测序（WES）将 以确定区分筛选检测到的惰性和非惰性之间的基因组特征。 侵袭性肺肿瘤导致临床结果不一致。来自110名患者的样本 将评估494例侵袭性癌症和494例惰性癌症沿着匹配的参考组织。通过 利用WES，我们将能够识别以前与肺癌无关的基因的影响， 作为已知在肺癌中起作用的基因的新等位基因。这将是第一个全面的基因组 在肺癌筛查过程中诊断的侵袭性和惰性肺癌的表征 审判对筛查肿瘤的详细基因组和基于成像的表征将最终 影响这些癌症的临床管理。通过单独的资助，我们还将整合基因组 通过本研究获得的肿瘤免疫微环境的数据（如通过多重免疫微环境表征的）， 同一标本的免疫荧光分析）和CT影像学特征建立综合， 肿瘤生物学的多参数模型，可用于预测肺癌的生物学行为， 筛选设置。

PROJECT SUMMARY/ABSTRACT The landmark NLST demonstrated a 20% mortality reduction in lung cancer in individuals who underwent low dose computed tomography (LDCT) screening relative to plain chest radiography. The results of the NLST have resulted in a sea change in US health policy, such that third party payers and Medicare now provide LDCT screening as a preventive service benefit in eligible, high risk smokers. Understanding the factors underlying tumor indolence or aggression that result in heterogeneous clinical outcomes, may facilitate clinical decision making in the context of lung cancer screening and thereby greatly increase its effectiveness. We hypothesize that the mutational landscape of screen-detected lung cancers is an important contributor to their indolence or aggressiveness. To address this hypothesis we will take advantage of the comprehensively annotated NLST biorepository. Whole exome sequencing (WES) of the previously collected NLST samples will be performed to determine the genomic features that distinguish between screen-detected indolent and aggressive lung tumors that result in heterogeneous clinical outcomes. Samples from 110 patients with aggressive cancers and 494 with indolent cancers along with matching reference tissues will be assessed. By utilizing WES, we will be able to identify the impact of genes not previously associated with lung cancer as well as novel alleles of genes with known roles in lung cancer. This will be the first comprehensive genomic characterization of aggressive and indolent lung cancers diagnosed in the course of a lung cancer screening trial. The detailed genomic and imaging-based characterization of screen-detected tumors will ultimately impact clinical management of those cancers. Through separate funding, we will also integrate the genomic data obtained through this research with the tumor immune microenvironment (as characterized by multiplex immunofluorescence analysis of the same specimens) and CT imaging features to build integrated, multiparametric models of tumor biology that can be used to predict the biological behavior of lung cancers in the screening setting.