Multi-omics Analysis Reveals Molecular Changes During Early Progression of Precancerous Lesions to Lung Adenocarcinoma in Never-Smokers

Abstract Lung cancer is the most common cause of cancer mortality globally, and the prevalence of lung adenocarcinoma (LUAD), the most common lung cancer subtype, has increased sharply in East Asia. Early diagnosis leads to better survival rates, but this requires an improved understanding of the molecular changes during early tumorigenesis, particularly in non-smokers. Here, we performed whole exome-sequencing and RNA-sequencing of samples from 94 East Asian patients with precancerous lesions (25 with atypical adenomatous hyperplasia [AAH]; 69 with adenocarcinoma in situ [AIS]) and 73 patients with early invasive lesions (minimally invasive adenocarcinoma [MIA]). Cellular analysis revealed that the activities of endothelial and stromal cells could be used to categorize tumors into molecular subtypes within pathologically defined types of lesions. The subtypes were linked with the radiologically defined type of lesions and corresponded to immune cell infiltration throughout the early progression of LUAD. Spatial transcriptomic analysis revealed the distribution of epithelial cells, endothelial cells, fibroblasts, and plasma cells within MIA samples. Characterization of the molecular lesion subtypes identified positively selected mutational patterns and suggested that angiogenesis in the late-stage AIS type potentially contributes to tissue invasion of the MIA type. This study offers a resource that may help to improve early diagnosis and patient prognosis, and the findings suggest possible approaches for early disease interception.