Abstract PR007: Molecular Subtyping of Lung Adenocarcinoma Premalignant Lesions Identifies Features Associated with Aggressive Disease

Abstract Lung cancer is the leading cause of cancer-related death. The five year survival rate had remained stagnant for decades, but more effective screening protocols using low-dose computed tomographic screening for high-risk individuals, along with progress in treatment for advanced-stage lung cancer with targeted therapy and immunotherapy, have helped decrease lung cancer mortality. However, improved approaches to lung cancer prevention and early detection are still urgently needed. Adenocarcinoma (LUAD) is the most common form of lung cancer. Following surgical resection of pre-invasive adenocarcinoma in situ, the five-year survival rate approaches 100%. This emphasizes the need for improved understanding of characteristics of aggressive premalignant lesions that would benefit from early interventions. In contrast to the well-characterized histopathologic sequence of lung squamous cell carcinoma, atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS) are the only known precursors in the sequence of LUAD pathogenesis. The features of AAH and AIS that lead to invasive LUAD are poorly characterized. The relationship of AIS and AAH to the histologically diverse subtypes of LUAD, ranging from the typically slow growing lepidic to aggressive solid subtypes, are also unclear. We hypothesized that transcriptomic changes in subsets of premalignant lesions are linked to distinct genomic and clinicopathologic features of malignant disease. To investigate this hypothesis, we performed exome sequencing and bulk RNA sequencing of laser capture microdissected tissue from tumor margins that included premalignant lesions, invasive tumor, and adjacent normal tissues. With our analysis, we discovered de novo subtypes of LUAD premalignant lesions based on gene expression. One of these subtypes had gene expression alterations similar to aggressive invasive LUAD solid tumors. This molecular adenomatous premalignant lesion subtype was also associated with an increased accumulation of cancer driver mutations. This subtype was further characterized by altered expression of immune-related pathways. Molecular signatures measured in adenomatous PML may thus enhance our understanding of pathway dysregulation and mutational heterogeneity occurring during LUAD carcinogenesis, and implicate immunotherapeutic strategies to prevent their progression to cancer. Citation Format: Kelley Anderson, Linh Tran, Kostyantyn Krysan, William Wallace, Gregory Fishbein, Emily Green, Gang Liu, Hanqiao Liu, Erin Kane, Sarah Mazzilli, Steven Dubinett, Avrum Spira, Marc Lenburg, Jennifer Beane. Molecular subtyping of lung adenocarcinoma premalignant lesions identifies features associated with aggressive disease [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr PR007.