Detecting the Presence and Progression of Premalignant Lung Lesions via Airway Gene Expression

Abstract

Lung cancer is the leading cause of cancer-related death in the United States. The molecular events preceding the onset of disease are poorly understood, and no effective tools exist to identify smokers with premalignant lesions (PMLs) that will progress to invasive cancer. Prior work identified molecular alterations in the smoke-exposed airway field of injury associated with lung cancer. Here, we focus on an earlier stage in the disease process leveraging the airway field of injury to study PMLs and its utility in lung cancer chemoprevention. Bronchial epithelial cells from normal appearing bronchial mucosa were profiled by mRNA-Seq from subjects with ( = 50) and without ( = 25) PMLs. Using surrogate variable and gene set enrichment analysis, we identified genes, pathways, and lung cancer-related gene sets differentially expressed between subjects with and without PMLs. A computational pipeline was developed to build and test a chemoprevention-relevant biomarker. We identified 280 genes in the airway field associated with the presence of PMLs. Among the upregulated genes, oxidative phosphorylation was strongly enriched, and IHC and bioenergetics studies confirmed pathway findings in PMLs. The relationship between PMLs and squamous cell carcinomas (SCC) was also confirmed using published lung cancer datasets. The biomarker performed well predicting the presence of PMLs (AUC = 0.92, = 17), and changes in the biomarker score associated with progression/stability versus regression of PMLs (AUC = 0.75, = 51). Transcriptomic alterations in the airway field of smokers with PMLs reflect metabolic and early lung SCC alterations and may be leveraged to stratify smokers at high risk for PML progression and monitor outcome in chemoprevention trials. .

Comprehensive analysis of tumour initiation, spatial and temporal progression under multiple lines of treatment

“…On the other hand, less common drivers tended to occur preferentially early in specific tumour subtypes. When our results are compared to previously reported models of progression from pre-malignant to malignant lung cancer (based on sampling pre-malignant lesions) 54 , we find similar patterns.…”

Malignant transformation rate of oral leukoplakia in an Australian population

“…In future, single‐cell transcriptomics may offer even greater value in understanding pre‐malignant lesions, where changes in gene expression are limited to a relatively small proportion of cells which may be too subtle to detect in bulk RNA sequencing. This has been demonstrated in pre‐malignant lung lesions among other cancers …”

“…In future, single-cell transcriptomics may offer even greater value in understanding pre-malignant lesions, where changes in gene expression are limited to a relatively small proportion of cells which may be too subtle to detect in bulk RNA sequencing. This has been demonstrated in pre-malignant lung lesions among other cancers 33. Relatively, few OPMDs will undergo MT, and clinical observation and histopathological assessment alone do not allow accurate prediction of which lesions will progress to malignancy.Exomic studies of OPMDs and their comparison with OSCC would allow an understanding of the process of oral carcinogenesis, in particular the accumulation and timing of specific mutations associated with malignancy.…”

Molecular Subtyping reveals Immune Alterations associated with Progression of Bronchial Premalignant Lesions

“…The Proliferative subtype is enriched with dysplastic PMLs from current smokers and is characterized by up-regulation of metabolic (OXPHOS/ETC/TCA) and cell cycle pathways and down-regulation of cilia-associated pathways. Previous work indicates increases in metabolic pathways in the airways of subjects with dysplastic lesions (13), in PMLs adjacent to LUSC tumor (24), and in smokers at high-risk for lung cancer (25) as well as increases in proliferation (via Ki67 levels, as mentioned above) that have been utilized as an endpoint in lung cancer chemoprevention (26,27). Identification of patients with Proliferative lesions may be useful to enrich lung cancer chemoprevention trials with high-risk subjects or to identify patients who would benefit from more frequent lung cancer screening.…”

“…Previously, we have shown that bronchial brushes from normal appearing areas of the mainstem bronchus could predict the presence of PMLs (13); however, that study lacked biopsies and brushes from the same subjects. Above, in both the DC and the VC biopsies, the Proliferative subtype, represents a distinct subtype of PMLs enriched for dysplastic histology expressing metabolic and proliferative pathways.…”