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Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients

Nature Medicine volume 23, pages 703713 (2017) | Download Citation

  • An Erratum to this article was published on 04 August 2017

This article has been updated

Abstract

Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The existence of recurrent targetable alterations across distinct histologically defined tumor types, coupled with an expanding portfolio of molecularly targeted therapies, demands flexible and comprehensive approaches to profile clinically relevant genes across the full spectrum of cancers. We established a large-scale, prospective clinical sequencing initiative using a comprehensive assay, MSK-IMPACT, through which we have compiled tumor and matched normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer and available pathological and clinical annotations. Using these data, we identified clinically relevant somatic mutations, novel noncoding alterations, and mutational signatures that were shared by common and rare tumor types. Patients were enrolled on genomically matched clinical trials at a rate of 11%. To enable discovery of novel biomarkers and deeper investigation into rare alterations and tumor types, all results are publicly accessible.

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Change history

  • 14 June 2017

    In the version of this article initially published online, the top value in the y axis of the Kaplan–Meier plots in Figure 3c was incorrectly denoted as 0.1. The correct value is 1. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We gratefully acknowledge C. England, J. Somar, T. Malbari, P. Salazar, S. Islam, E. Gallagher, I. Rijo, N. Mensah, G. Lukose, T. Mitchell, A. Yannes, Y. Chekaluk, G. Jour, N. Sadri, K. Tian, C. Pagan, J.K. Killian, D. Alex, J. Gomez-Gelvez, C. Ho, S. Naupari, J. Arlequin, C. Carvajal, L. Tovar Ramirez, J. Bakas, P. Sukhadia, E. Paraiso and J. Rudolph for their important contributions. This study was supported by the MSK Cancer Center Support Grant (P30 CA008748), Cycle for Survival, the Farmer Family Foundation, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology.

Author information

Author notes

    • Donavan T Cheng
    •  & Raghu Chandramohan

    Present addresses: Illumina, Inc., San Francisco, California, USA (D.T.C.) and Baylor College of Medicine, Houston, Texas, USA (R. Chandramohan).

    • Ahmet Zehir
    •  & Ryma Benayed

    These authors contributed equally to this work.

Affiliations

  1. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Ahmet Zehir
    • , Ryma Benayed
    • , Ronak H Shah
    • , Aijazuddin Syed
    • , Sumit Middha
    • , Hyunjae R Kim
    • , Preethi Srinivasan
    • , Meera Hameed
    • , Snjezana Dogan
    • , Dara S Ross
    • , Jaclyn F Hechtman
    • , Deborah F DeLair
    • , JinJuan Yao
    • , Diana L Mandelker
    • , Donavan T Cheng
    • , Raghu Chandramohan
    • , Abhinita S Mohanty
    • , Ryan N Ptashkin
    • , Gowtham Jayakumaran
    • , Meera Prasad
    • , Mustafa H Syed
    • , Anoop Balakrishnan Rema
    • , Zhen Y Liu
    • , Khedoudja Nafa
    • , Laetitia Borsu
    • , Justyna Sadowska
    • , Jacklyn Casanova
    • , Ruben Bacares
    • , Iwona J Kiecka
    • , Anna Razumova
    • , Julie B Son
    • , Lisa Stewart
    • , Tessara Baldi
    • , Kerry A Mullaney
    • , Hikmat Al-Ahmadie
    • , Efsevia Vakiani
    • , Niedzica Camacho
    • , Helen H Won
    • , David S Klimstra
    • , Maria E Arcila
    • , Marc Ladanyi
    •  & Michael F Berger
  2. Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Jianjiong Gao
    • , Debyani Chakravarty
    • , Benjamin E Gross
    • , Ritika Kundra
    • , Zachary J Heins
    • , Hsiao-Wei Chen
    • , Sarah Phillips
    • , Hongxin Zhang
    • , Jiaojiao Wang
    • , Angelica Ochoa
    • , Barry S Taylor
    • , Nikolaus Schultz
    • , David B Solit
    •  & Michael F Berger
  3. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Sean M Devlin
    • , Adam A Abeshouse
    • , Alexander V Penson
    • , Philip Jonsson
    • , Matthew T Chang
    • , Barry S Taylor
    •  & Nikolaus Schultz
  4. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Matthew D Hellmann
    • , Alison M Schram
    • , Wassim Abida
    • , Andrea Cercek
    • , Darren R Feldman
    • , Mrinal M Gounder
    • , James J Harding
    • , Gopa Iyer
    • , Yelena Y Janjigian
    • , Emmet J Jordan
    • , Ciara M Kelly
    • , Maeve A Lowery
    • , Nitya Raj
    • , Pedram Razavi
    • , Alexander N Shoushtari
    • , Tara E Soumerai
    • , Anna M Varghese
    • , Rona Yaeger
    • , Gregory J Riely
    • , Leonard B Saltz
    • , Howard I Scher
    • , Paul J Sabbatini
    • , Mark E Robson
    • , Jose Baselga
    • , David M Hyman
    •  & David B Solit
  5. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • David A Barron
  6. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Alexander V Penson
    • , Philip Jonsson
    • , Matthew T Chang
    • , Barry S Taylor
    • , Jose Baselga
    • , Nikolaus Schultz
    • , David B Solit
    • , Marc Ladanyi
    •  & Michael F Berger
  7. Information Systems, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Jonathan Wills
    • , Michael Eubank
    • , Stacy B Thomas
    •  & Stuart M Gardos
  8. Clinical Research Administration, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Dalicia N Reales
    • , Jesse Galle
    • , Robert Durany
    • , Roy Cambria
    • , Jonathan Coleman
    •  & Bernard Bochner
  9. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • A Ari Hakimi
    •  & Luc G T Morris
  10. Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Antonio M Omuro
  11. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Neerav Shukla

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Contributions

A.Z., R. Benayed and M.F.B. wrote the manuscript. R. Benayed, J.S., J. Casanova, R. Bacares, I.J.K., A.R., J.B.S., L.S., T.B. and K.A.M. generated the genomic data. A.Z., R. Benayed, R.H.S., S.M., H.R.K., P.S., S.M.D., M.H., S.D., D.S.R., J.F.H., D.F.D., J.Y., D.L.M., D.T.C., R. Chandramohan, A.S.M., R.N.P., G.J., K.N., L.B., P.J., N.C., M.T.C., H.H.W., B.S.T., N.S., D.M.H., M.E.A., D.B.S., M.L. and M.F.B. reviewed and analyzed the genomic data. M.D.H., D.A.B., A.M.S., H.A.-A., E.V., J.W., M.E., S.B.T., S.M.G., D.N.R., J. Galle, R.D., R. Cambria, W.A., A.C., D.R.F., M.M.G., A.A.H., J.J.H., G.I., Y.Y.J., E.J.J., C.M.K., M.A.L., L.G.T.M., A.M.O., N.R., P.R., A.N.S., N.S., T.E.S., A.M.V., R.Y., D.M.H. and D.B.S. provided clinical data. A.Z., A.S., J. Gao, D.C., D.T.C., M.P., M.H.S., A.B.R., Z.Y.L., A.A.A., A.V.P., B.E.G., R.K., Z.J.H., H.-W.C., S.P., H.Z., J.W., A.O., B.S.T. and N.S. created bioinformatics tools and systems to support data analysis, annotation and dissemination. J. Coleman, B.B., G.J.R., L.B.S., H.I.S., P.J.S., D.S.K., J.B. and D.B.S. provided support for the MSK-IMPACT sequencing initiative. M.E.R., D.M.H. and D.B.S. developed the institutional molecular profiling protocol. All authors reviewed the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michael F Berger.

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DOI

https://doi.org/10.1038/nm.4333

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