Journal
NATURE MEDICINE
Volume 25, Issue 3, Pages 517-+Publisher
NATURE RESEARCH
DOI: 10.1038/s41591-018-0323-0
Keywords
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Funding
- Wellcome Trust fellowships
- Rosetrees Trust
- Welton Trust
- Garfield Weston Trust
- Stoneygate Trust
- UCLH Charitable Foundation
- Roy Castle Lung Cancer Foundation
- Wellcome Trust clinical PhD training fellowship
- Wellcome Trust Sanger Institute non-clinical PhD studentship
- Department of Health's NIHR Biomedical Research Centre
- Stand Up to Cancer
- MRC [G108/596] Funding Source: UKRI
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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.
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