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

摘要： 肺癌仍然是全球癌症死亡的主要原因，主要是因为我们无法检测到 在疾病的最早阶段，以及在高危人群中缺乏预防其发展的干预措施。 开发新的肺癌检测和预防方法的速度限制步骤是我们缺乏 了解与肺癌发生相关的最早的分子和细胞变化。我们建议 建立高分辨率、多维的肺癌前病变的遗传、分子和细胞图谱 肺鳞癌和腺癌的病变及其周围微环境 肺癌有两种最常见的亚型。我们将利用独特的回顾和未来队列 通过我们的生物显微镜单元在多个医疗中心集合，以收集、注释和处理癌前病变 肺部和呼吸道的病损生物标本。我们的表征单位将应用现有的和新兴的 分子图谱工具，以描述这些损伤的基因组、转录和蛋白质组图景。 将建立标准化多维数据处理、质量控制、分析和集成的管道 由我们的数据分析股开发，导致创建一个基于网络的门户网站，用于数据传播和 在线综合分析，以造福于更大的研究社区。横断面抽样调查 与早期癌症相邻的癌前鳞状细胞和腺瘤性病变将使 空间地图，将提供对癌前细胞及其微环境演变的洞察。我们的 进展或退行的呼吸道癌前鳞状病变的纵向研究 浸润性癌将提供侵袭性分子决定因素的时间和空间图谱。 癌症。我们还将利用这项纵向研究来证明我们的肺前病变的临床效用。 癌症图谱通过开发可应用的癌前进展的预后生物标记物 临床上用于精确管理，以及对患有侵袭性癌前鳞状细胞的患者进行分层 病变进入早期干预试验。地图集的成功完成将因以下原因而加快：(1)a 高度协调的行政核心，将促进单位内部和单位之间的互动，以及 与HTAN内的其他中心交换数据、方法和工具；以及(2)与正在进行的合作 NCI、基金会和行业肺癌癌前倡议。我们的肺癌前图谱最终将服务于 作为医学界和科学界的一种资源，使早期生物标志物的开发成为可能 检测和风险分层，以及确定新的治疗目标，这些治疗将拦截 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.