Journal Article

Deciphering the genomic, epigenomic, and transcriptomic landscapes of pre-invasive lung cancer lesions

Chandrasekharan, Deepak, Morris, Tiffany J., Capitanio, Arrigo, Brown, James M., Thirlwell, Christina, Janes, Sam M., Spira, Avrum, Beck, Stephan, Chambers, Rachel C., Navani, Neal, Farmery, Henry, Lee-Six, Henry, Falzon, Mary, Paul, Dirk S., Ntolios, Paschalis, Feber, Andrew, McGranahan, Nicholas, Pipinikas, Christodoulos P., Hynds, Robert E., Durrenberger, Pascal F., George, Phillip Jeremy, Lynch, Andy G., Karpathakis, Anna, Swanton, Charles, Carroll, Bernadette, Pennycuick, Adam, Campbell, Peter J., Breeze, Charles E., Beane, Jennifer, Teixeira, Vitor H., Thakrar, Ricky M., Hardavella, Georgia

2019

Overview

The molecular alterations that occur in cells before cancer is manifest are largely uncharted. Lung carcinoma in situ (CIS) lesions are the pre-invasive precursor to squamous cell carcinoma. Although microscopically identical, their future is in equipoise, with half progressing to invasive cancer and half regressing or remaining static. The cellular basis of this clinical observation is unknown. Here, we profile the genomic, transcriptomic, and epigenomic landscape of CIS in a unique patient cohort with longitudinally monitored pre-invasive disease. Predictive modeling identifies which lesions will progress with remarkable accuracy. We identify progression-specific methylation changes on a background of widespread heterogeneity, alongside a strong chromosomal instability signature. We observed mutations and copy number changes characteristic of cancer and chart their emergence, offering a window into early carcinogenesis. We anticipate that this new understanding of cancer precursor biology will improve early detection, reduce overtreatment, and foster preventative therapies targeting early clonal events in lung cancer. A multi-omics survey of progressive compared to regressive carcinoma in situ lesions provides a molecular map of early lung cancer development.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/212/177 / 631/67/1612/1350 / 692/420/755 / 692/699/67/69 / Adult / Aged / Aged, 80 and over / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer genetics / Cancer invasiveness / Cancer Research / Carcinogenesis / Carcinogenesis - genetics / Carcinogens / Carcinoma / Carcinoma in Situ - genetics / Carcinoma, Squamous Cell - genetics / Chromosomal Instability - genetics / Cohort Studies / Copy number / Development and progression / Disease Progression / DNA Copy Number Variations / DNA Methylation - genetics / Epigenomics / Female / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Genetic aspects / Genomic instability / Genomics / Heterogeneity / Humans / Infectious Diseases / Invasiveness / Landscape / Lesions / Longitudinal Studies / Lung cancer / Lung carcinoma / Lung Neoplasms - genetics / Lungs / Male / Medical schools / Metabolic Diseases / Methylation / Middle Aged / Molecular Medicine / Mutation / Neurosciences / Patient monitoring equipment / Precursors / Prediction models / Preventive medicine / Resource / Squamous cell carcinoma / Squamous cell tumors / Stability / Transcriptomics