IA06 Intercepting Lung Cancer by Understanding Premalignant Changes in the Airway Field

Abstract

Lung cancer is the leading cause of cancer death. In order to decrease mortality, we need innovative strategies to intercept cancer development by diagnosing the disease at its earliest and potentially most curable stage. Development of lung cancer risk biomarkers and interception strategies requires a detailed understanding of the earliest molecular alterations involved in lung carcinogenesis that occur in the respiratory epithelium. Exposure to cigarette smoke creates a field of injury throughout the entire respiratory tract by inducing a variety of genomic alterations that can lead to an at-risk airway where lung squamous premalignant lesions develop. Lung squamous cell carcinoma arises in the epithelial layer of the bronchial airways and is often preceded by the development of premalignant lesions through a stepwise histologic progression from normal epithelium to hyperplasia, squamous metaplasia, dysplasia (mild, moderate, and severe), carcinoma in situ, and finally to invasive cancer. The presence of high-grade persistent or progressive dysplasia is a marker of increased lung cancer risk, although many lesions have varied outcomes. Recent molecular profiling of endobronchial biopsies representing a range of histologic scores revealed an upregulation of cell cycle, proliferation, and DNA repair pathways and downregulation of inflammation and immune-associated pathways in high-grade progressive/persistent lesions. This work provided a foundation with which to further our understanding of the mechanisms that drive these early alterations and to develop robust biomarkers to detect their presence and future behavior. Recent projects that build upon this work to elucidate the pathways responsible for histologic progression will be presented. These projects will be put into the context of the collaborative effort to create a lung precancer atlas that will include large-scale genomic, immunogenomic, and clinical multidimensional data. This larger effort will serve to both validate existing observations and biomarkers and further enhance lung cancer interception efforts.