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

An Erratum to this article was published on 01 August 2017

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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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Figure 1: Overview of the MSK-IMPACT clinical workflow.
Figure 2: Overview of the MSK-IMPACT cohort.
Figure 3: The spectrum of TERT promoter mutations in cancer.
Figure 4: Spectrum of kinase fusions identified by MSK-IMPACT.
Figure 5: Mutational signatures derived from MSK-IMPACT targeted sequencing data.
Figure 6: Clinical actionability of somatic alterations revealed by MSK-IMPACT.

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.

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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.

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Correspondence to Michael F Berger.

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Zehir, A., Benayed, R., Shah, R. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med 23, 703–713 (2017). https://doi.org/10.1038/nm.4333

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