Deciphering the genomic, epigenomic, and transcriptomic landscapes of pre-invasive lung cancer lesions
Authors listVitor H Teixeira Christodoulos P Pipinikas Adam Pennycuick Henry Lee-Six Deepak Chandrasekharan Jennifer Beane Tiffany J Morris Anna Karpathakis Andrew Feber Charles E Breeze Paschalis Ntolios Rob Hynds Mary Falzon Arrigo Capitanio Bernadette Carroll Pascal F Durrenberger Georgia Hardavella James M Brown Andy G Lynch Henry Farmery Dirk S Paul Rachel C Chambers Nicholas McGranahan Neal Navani Ricky M Thakrar Charles Swanton Stephan Beck Phillip Jeremy George Avrum Spira Peter J Campbell Christina Thirlwell Sam M Janes
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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.
Journal Nature Medicine
Issue number 3