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

Vitor H. Texeira; Chrisodoulos P. Pipinikas; Adam Pennycuick; Henry Lee-Six; Deepak Chandrasekharan; Jennifer Beane; Tiffany J. Morris; Anna Karpathakis; Andrew Feber; Charles E. Breeze; Paschalis Ntolios; Robert E. 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; Philip Jeremy George; Avrum Spira; Peter J. Campbell; Christina Thirwell; Sam M. Janes

doi:10.1038/s41591-018-0323-0

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

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

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	517-525
Number of pages	9
Journal	Nature Medicine
Volume	25
Issue number	3
Early online date	21 Jan 2019
DOIs	https://doi.org/10.1038/s41591-018-0323-0
Publication status	Published - Mar 2019

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10.1038/s41591-018-0323-0

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Copyright © 2019, the Author(s). This work is made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1038/s41591-018-0323-0
Accepted author manuscript, 63.4 MB

Andy Lynch
- andy.lynchst-andrews.acuk
- School of Mathematics and Statistics - Professor
- School of Medicine - Professor of Statistics in Bioscience
- Sir James Mackenzie Institute for Early Diagnosis
- St Andrews Bioinformatics Unit
- Cellular Medicine Division
Person: Academic

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Texeira, V. H., Pipinikas, C. P., Pennycuick, A., Lee-Six, H., Chandrasekharan, D., Beane, J., Morris, T. J., Karpathakis, A., Feber, A., Breeze, C. E., Ntolios, P., Hynds, R. E., Falzon, M., Capitanio, A., Carroll, B., Durrenberger, P. F., Hardavella, G., Brown, J. M., Lynch, A. G., ... Janes, S. M. (2019). Deciphering the genomic, epigenomic and transcriptomic landscapes of pre-invasive lung cancer lesions. Nature Medicine, 25(3), 517-525. https://doi.org/10.1038/s41591-018-0323-0

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

abstract = "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.",

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

year = "2019",

month = mar,

doi = "10.1038/s41591-018-0323-0",

language = "English",

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pages = "517--525",

journal = "Nature Medicine",

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Texeira, VH, Pipinikas, CP, Pennycuick, A, Lee-Six, H, Chandrasekharan, D, Beane, J, Morris, TJ, Karpathakis, A, Feber, A, Breeze, CE, Ntolios, P, Hynds, RE, Falzon, M, Capitanio, A, Carroll, B, Durrenberger, PF, Hardavella, G, Brown, JM, Lynch, AG, Farmery, H, Paul, DS, Chambers, RC, McGranahan, N, Navani, N, Thakrar, RM, Swanton, C, Beck, S, George, PJ, Spira, A, Campbell, PJ, Thirwell, C & Janes, SM 2019, 'Deciphering the genomic, epigenomic and transcriptomic landscapes of pre-invasive lung cancer lesions', Nature Medicine, vol. 25, no. 3, pp. 517-525. https://doi.org/10.1038/s41591-018-0323-0

TY - JOUR

T1 - Deciphering the genomic, epigenomic and transcriptomic landscapes of pre-invasive lung cancer lesions

AU - Texeira, Vitor H.

AU - Pipinikas, Chrisodoulos P.

AU - Pennycuick, Adam

AU - Lee-Six, Henry

AU - Chandrasekharan, Deepak

AU - Beane, Jennifer

AU - Morris, Tiffany J.

AU - Karpathakis, Anna

AU - Feber, Andrew

AU - Breeze, Charles E.

AU - Ntolios, Paschalis

AU - Hynds, Robert E.

AU - Falzon, Mary

AU - Capitanio, Arrigo

AU - Carroll, Bernadette

AU - Durrenberger, Pascal F.

AU - Hardavella, Georgia

AU - Brown, James M.

AU - Lynch, Andy G.

AU - Farmery, Henry

AU - Paul, Dirk S.

AU - Chambers, Rachel C.

AU - McGranahan, Nicholas

AU - Navani, Neal

AU - Thakrar, Ricky M.

AU - Swanton, Charles

AU - Beck, Stephan

AU - George, Philip Jeremy

AU - Spira, Avrum

AU - Campbell, Peter J.

AU - Thirwell, Christina

AU - Janes, Sam M.

PY - 2019/3

Y1 - 2019/3

N2 - 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.

AB - 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.

U2 - 10.1038/s41591-018-0323-0

DO - 10.1038/s41591-018-0323-0

M3 - Article

SN - 1078-8956

VL - 25

SP - 517

EP - 525

JO - Nature Medicine

JF - Nature Medicine

IS - 3

ER -

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

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