The Lung PCA: A Multi-Dimensional Atlas of Pulmonary Premalignancy

摘要： 肺癌仍然是世界范围内癌症死亡率的主要原因，主要是由于我们无法检测到肺癌的发生。 这一问题的根源在于疾病处于最早阶段，以及缺乏干预措施来预防高危人群的疾病发展。 发展肺癌检测和预防新方法的限速步骤是我们缺乏 了解与肺癌发生相关的最早期分子和细胞变化。我们提出 开发一个高分辨率，多维的基因，分子和细胞图谱的癌前肺 肺鳞状细胞癌和腺癌的病变及其周围微环境， 两种最常见的肺癌亚型。我们将利用独特的回顾性和前瞻性队列 通过我们的生物标本部门在多个医疗中心集合，收集、注释和处理癌前病变 肺和气道的病变生物标本。我们的表征单元将应用现有的和新兴的 分子分析工具来表征这些病变的基因组、转录组和蛋白质组景观。 标准化多维数据处理、质量控制、分析和整合的管道将 由我们的数据分析股开发，导致创建一个基于网络的数据传播门户， 在线综合分析，使更大的研究社区受益。横截面抽样 邻近早期癌症的癌前鳞状和腺瘤性病变将使发展成为一种恶性肿瘤。 空间地图，将提供深入了解癌前细胞及其微环境的演变。我们 气道癌前鳞状病变进展或消退的纵向研究 侵袭性癌将提供侵袭性肿瘤的分子决定因素的时间和空间图， carcinoma.我们还将利用这项纵向研究来证明我们的肺预处理的临床效用， 癌症图谱通过开发可应用的癌前进展的预后生物标志物 临床上用于精确管理，以及对侵袭性癌前鳞状细胞癌患者进行分层 进行早期干预试验。将通过以下方式加快地图集的成功完成： 高度协调的行政核心，将促进内部和跨单位的互动，以及 与HTAN内的其他中心交换数据、方法和工具;（2）与正在进行的 NCI、基金会和行业肺癌前病变倡议。我们的肺癌前期图谱将最终服务于 作为医学和科学界的资源，使生物标志物的发展，为早期 检测和风险分层，以及识别新的治疗靶点， 肺癌的发展。

Abstract: Lung cancer remains the leading cause of cancer mortality worldwide chiefly due to our inability to detect the disease at its earliest stage and the lack of interventions to prevent its development in those at highest risk. The rate-limiting step to developing new approaches for lung cancer detection and prevention is our lack of understanding of the earliest molecular and cellular changes associated with lung carcinogenesis. We propose to develop a high-resolution, multidimensional genetic, molecular, and cellular atlas of pre-cancerous lung lesions and their surrounding microenvironment for lung squamous cell carcinoma and adenocarcinoma, the two most common subtypes of lung cancer. We will leverage unique retrospective and prospective cohorts assembled at multiple medical centers via our Biospecimen Unit to collect, annotate, and process premalignant lesion biospecimens of the lung and airway. Our Characterization Unit will apply existing and emerging molecular profiling tools to characterize the genomic, transcriptomic, and proteomic landscape of these lesions. Pipelines for standardized multidimensional data processing, quality control, analysis and integration will be developed by our Data Analysis Unit, leading to creation of a web-based portal for data dissemination and online integrative analysis to benefit the greater research community. Cross-sectional sampling of premalignant squamous and adenomatous lesions adjacent to early stage cancer will enable development of a spatial map that will provide insights into the evolution of premalignant cells and their microenvironment. Our longitudinal study of airway premalignant squamous lesions that progress toward or regress away from invasive carcinoma will provide both a temporal and spatial map of the molecular determinants of invasive carcinoma. We will also leverage this longitudinal study to demonstrate the clinical utility of our Lung Pre- Cancer Atlas through development of prognostic biomarkers of premalignant progression that can be applied clinically for precision management, as well as to stratify patients with aggressive premalignant squamous lesions into early-phase intervention trials. Successful completion of the Atlas will be accelerated by: (1) a highly-coordinated Administrative Core that will facilitate interactions within and across Units, as well as the exchange of data, methods, and tools with other centers within the HTAN; and (2) partnerships with ongoing NCI, foundation, and industry lung premalignancy initiatives. Our Lung Pre-Cancer Atlas will ultimately serve as a resource for the medical and scientific communities to enable the development of biomarkers for early detection and risk stratification, as well as identification of novel targets for therapies that will intercept the development of lung cancer.