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Gene expression–based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study

Nature Medicine volume 14, pages 822827 (2008) | Download Citation

Abstract

Although prognostic gene expression signatures for survival in early-stage lung cancer have been proposed, for clinical application, it is critical to establish their performance across different subject populations and in different laboratories. Here we report a large, training–testing, multi-site, blinded validation study to characterize the performance of several prognostic models based on gene expression for 442 lung adenocarcinomas. The hypotheses proposed examined whether microarray measurements of gene expression either alone or combined with basic clinical covariates (stage, age, sex) could be used to predict overall survival in lung cancer subjects. Several models examined produced risk scores that substantially correlated with actual subject outcome. Most methods performed better with clinical data, supporting the combined use of clinical and molecular information when building prognostic models for early-stage lung cancer. This study also provides the largest available set of microarray data with extensive pathological and clinical annotation for lung adenocarcinomas.

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Acknowledgements

We thank M. Orringer, A. Pickens, F. Taylor, N. Liu, D. Lau, M. Whitehead, L. Chen, L. Vargas, Y. Xiao, M. Maddaus and C. Hoang. We thank M. Heiskanen, L. Liu, D. Reeves and S. Whitley from the US National Cancer Institute Center for Bioinformatics and W. Ricker from Information Management Services for assistance with development of the lung study database and data management. We thank D. Sawyer, J.M. Askew and A. Vaughn of the Cancer and Leukemia Group B Statistical Center, Duke University for quality control of the clinical data. We thank Affymetrix for technical support. This work was supported by US National Cancer Institute grants CA84953, CA84999, CA84995, CA85052 and CA46592 and contracts 263-MQ-319735, 263-MQ-319740, 263-MQ-319746 and 263-MQ-510430 and support from the Canadian Cancer Society.

Author information

Author notes

    • Kerby Shedden
    • , Jeremy M G Taylor
    • , Steven A Enkemann
    • , Ming-Sound Tsao
    • , Timothy J Yeatman
    • , William L Gerald
    • , Steven Eschrich
    • , Igor Jurisica
    • , Venkatraman E Seshan
    • , Matthew Meyerson
    • , Rork Kuick
    • , Kevin K Dobbin
    • , Tracy Lively
    • , James W Jacobson
    •  & David G Beer

    Writing Committee members.

Affiliations

  1. Department of Statistics, 1085 South University, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Kerby Shedden
  2. Cancer Center, 1500 East Medical Center Drive, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Kerby Shedden
    • , Jeremy M G Taylor
    • , David E Misek
    • , Andrew C Chang
    • , Samir Hanash
    • , Rork Kuick
    •  & David G Beer
  3. Department of Biostatistics, 1420 Washington Heights, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Jeremy M G Taylor
  4. Department of Surgery, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Avenue, Tampa, Florida 33612, USA.

    • Steven A Enkemann
    • , Timothy J Yeatman
    • , Steven Eschrich
    • , Michael Gruidl
    •  & Anupama Sharma
  5. University Health Network, Ontario Cancer Institute and Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada.

    • Ming-Sound Tsao
    • , Igor Jurisica
    • , Chang Qi Zhu
    • , Daniel Strumpf
    •  & Frances A Shepherd
  6. Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.

    • William L Gerald
    • , Janos Szoke
    • , Maureen Zakowski
    • , Valerie Rusch
    • , Mark Kris
    • , Agnes Viale
    • , Noriko Motoi
    •  & William Travis
  7. Department of Pathology, University Hospital 2G332/0054, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Thomas J Giordano
  8. Department of Surgery, 1150 West Medical Center Drive, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • David E Misek
    • , Andrew C Chang
    •  & David G Beer
  9. National Cancer Institute of Canada Clinical Trials Group and Queen's University, 10 Stuart Street, Kingston, Ontario K7L 3N6, Canada.

    • Keyue Ding
    •  & Lesley Seymour
  10. Department of Medical Oncology, Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts, 02115, USA.

    • Katsuhiko Naoki
    • , Nathan Pennell
    • , Barbara Weir
    • , Roel Verhaak
    •  & Matthew Meyerson
  11. Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.

    • Christine Ladd-Acosta
    • , Todd Golub
    •  & Matthew Meyerson
  12. Department of Medicine, B-414 Clinical Center, Michigan State University, East Lansing, Michigan 48824, USA.

    • Barbara Conley
  13. Columbia University, 722 West 168th Street, New York, New York 10032, USA.

    • Venkatraman E Seshan
  14. Biometric Research Branch National Cancer Institute, EPN 8121A, 6130 Executive Boulevard, Rockville, Maryland 20852, USA.

    • Kevin K Dobbin
  15. Cancer Diagnosis Program, National Cancer Institute, EPN 6035A, 6130 Executive Boulevard, Rockville, Maryland 20852, USA.

    • Tracy Lively
    •  & James W Jacobson

Consortia

  1. Director's Challenge Consortium for the Molecular Classification of Lung Adenocarcinoma

    The consortium consists of the Writing Committee plus additional participants as detailed in the Author Contributions section.

Authors

    Contributions

    Writing Committee: K.S., J.M.G.T., S.A.E., M.S.T., T.J.Y., W.L.G., S.E., I.J., V.E.S., M.M., R.K., K.K.D., T.L., J.W.J. and D.G.B. Members of the Writing Committee participated in the planning, initiation, data generation, data analysis and manuscript preparation for the project.

    Additional participants: T.J.G., D.E.M., A.C.C. and S.H. participated in aspects of sample collection and preparation, data generation and data analysis at the University of Michigan. C.Q.Z., D.S., F.A.S., K.D. and L.S. participated in aspects of sample collection and preparation, data generation and data analysis at the Ontario Cancer Institute. K.N., N.P., B.W., R.V., C.L.-A and T.G. participated in aspects of sample collection and preparation, data generation and data analysis at the Dana-Farber Cancer Institute and Broad Institute. M.G. assembled the clinical data at the H. Lee Moffitt Cancer Center. J.S., M.Z., V.R., M.K., A.V., N.M., W.T. and A.S. participated in aspects of sample collection and preparation, data generation and data analysis at Memorial Sloan-Kettering Cancer Center. B.C. participated in the planning and initiation of the study.

    Corresponding authors

    Correspondence to James W Jacobson or David G Beer.

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    DOI

    https://doi.org/10.1038/nm.1790

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