Archetype Analysis of Lung Adenocarcinoma Premalignancy Links Heterogeneity in Premalignant Lesions to Diverging Features of Invasive Disease

Lung adenocarcinoma (LUAD), the most common subtype of lung cancer, is a heterogeneous disease with highly variable histopathologic features and clinical outcomes. LUAD premalignant lesions (PML) are localized proliferations of atypical pneumocytes that spread along the alveolar walls. In this study, we characterized the molecular heterogeneity across PMLs, regardless of histologic classification, and identified four distinct groups or "archetypes" of PMLs using bulk RNA and DNA exome sequencing data from laser-captured microdissected PMLs, normal, and tumor tissues from LUAD resection cases. The archetypes were defined byrecurrent gene coexpression modules discovered using the LUAD PMLs we profiled and three publicly available datasets. One PML archetype, termed "proliferation," was associated with increased expression of genes involved in cell proliferation, a protumor immune environment, and enrichment for EGFR driver mutations. In contrast, the "normal-like" archetype exhibited molecular features similar to normal tissue, an antitumor immune response, and lacked driver mutation enrichment. We projected the PML archetypes into independent gene expression datasets profiling LUAD and found that tumors closest to the proliferation archetype were enriched for multiple features of aggressive LUAD, including high tumor grade and lymph node invasion, and were significantly associated with shorterdisease-free survival. Proliferation archetype PMLs may represent a subset of lesions with increased malignant potential and may provide opportunities to improve patient stratification and identify novel targets for lung cancer interception. IMPLICATIONS: Molecular signatures that distinguish indolent from aggressive LUAD PMLs may help personalize lung cancer screening and interception protocols.