Abstract

Metastasis is the primary cause of cancer-related deaths. Although The Cancer Genome Atlas has sequenced primary tumour types obtained from surgical resections, much less comprehensive molecular analysis is available from clinically acquired metastatic cancers. Here we perform whole-exome and -transcriptome sequencing of 500 adult patients with metastatic solid tumours of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53, CDKN2A, PTEN, PIK3CA, and RB1. Putative pathogenic germline variants were present in 12.2% of cases of which 75% were related to defects in DNA repair. RNA sequencing complemented DNA sequencing to identify gene fusions, pathway activation, and immune profiling. Our results show that integrative sequence analysis provides a clinically relevant, multi-dimensional view of the complex molecular landscape and microenvironment of metastatic cancers.

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Acknowledgements

This work was supported by a National Institutes of Health (NIH) Clinical Sequencing Exploratory Research Award NIH 1UM1HG006508. Other sources of support included the Prostate Cancer Foundation, Stand Up 2 Cancer (SU2C)-Prostate Cancer Foundation Prostate Dream Team Grant SU2C-AACR-DT0712, Early Detection Research Network grant U01 CA214170, and Prostate SPORE grant P50 CA186786. A.M.C. is a Howard Hughes Medical Institute Investigator, A. Alfred Taubman Scholar, and American Cancer Society Professor. M.C. is supported by a PCF Young Investigator Award. We acknowledge Y. Ning, R. Wang, X. Dang, M. Davis, L. Hodges, J. Griggs, J. Athanikar, C. Brennan, C. Betts, J. Chen, S. Kalyana-Sundaram, K. Giles, and R. Mehra for their contributions to this study. Over 100 physicians referred patients to this study and we acknowledge the following: K. Cooney, M. Hussain, S. Urba, N. Henry, V. Sahai, D. Simeone, C. Lao, J. Smerage, M. Caram, M. Burness, G. Kalemkerian, C. Van Poznak, M. Wicha, R. Buckanovich, J. Bufill, P. Grivas, P. Hu, A. Morikawa, P. Palmbos, B. Redman, F. Feng, G. Hammer, S. Merajver, and A. Pearson. We thank S. Roychowdhury and K. Pienta for help in protocol development for the MI-ONCOSEQ program. Most importantly, we recognize the generosity and kindness of the cancer patients and their families for participating in this study.

Author information

Author notes

    • Dan R. Robinson
    • , Yi-Mi Wu
    • , Robert J. Lonigro
    •  & Marcin Cieślik

    These authors contributed equally to this work.

Affiliations

  1. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA

    • Dan R. Robinson
    • , Yi-Mi Wu
    • , Robert J. Lonigro
    • , Pankaj Vats
    • , Xuhong Cao
    • , Erica Rabban
    • , Chandan Kumar-Sinha
    • , Javed Siddiqui
    • , Scott A. Tomlins
    • , Lakshmi P. Kunju
    • , Marcin Cieślik
    •  & Arul M. Chinnaiyan
  2. Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA

    • Dan R. Robinson
    • , Yi-Mi Wu
    • , Chandan Kumar-Sinha
    • , Javed Siddiqui
    • , Scott A. Tomlins
    • , David Lucas
    • , Lakshmi P. Kunju
    • , Marcin Cieślik
    •  & Arul M. Chinnaiyan
  3. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA

    • Erin Cobain
    • , Jessica Everett
    • , Victoria Raymond
    • , Scott Schuetze
    • , Ajjai Alva
    • , Rashmi Chugh
    • , Francis Worden
    • , Mark M. Zalupski
    • , Laurence H. Baker
    • , Nithya Ramnath
    • , Ann F. Schott
    • , Daniel F. Hayes
    • , Elena M. Stoffel
    •  & David C. Smith
  4. Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA

    • Jeffrey Innis
    •  & Rajen J. Mody
  5. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Joseph Vijai
    •  & Kenneth Offit
  6. Department of Health Behavior & Health Education, School of Public Health, University of Michigan, Ann Arbor, Michigan 48109, USA

    • J. Scott Roberts
  7. Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA

    • Moshe Talpaz
    •  & Arul M. Chinnaiyan
  8. Department of Urology, University of Michigan, Ann Arbor, Michigan 48109, USA

    • Arul M. Chinnaiyan
  9. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA

    • Arul M. Chinnaiyan

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Contributions

D.R.R., Y.-M.W., and X.C. coordinated clinical sequencing. R.J.L., M.C., and P.V. developed the bioinformatics analysis. J.S. coordinated sample procurement, L.P.K., D.L., and S.A.T. led the histopathology analysis. D.C.S., S.S., M.M.Z., A.A., R.C., F.W., L.H.B., R.J.M., N.R., A.F.S., and D.F.H. coordinated patient recruitment. E.R. was the lead study coordinator. J.E., V.R., E.M.S., and J.I. provided genetic counselling and assessment of PPGMs, and J.V. and K.O. analysed relative risk assessment. J.S.R. coordinated the bioethics component. M.T. and A.M.C. coordinated IRB protocol development. D.R.R., Y.-M.W. and C.K.-S. prepared PMTBs. E.C., M.T., D.F.H., D.R.R., and Y.-M.W. implemented the clinical tiering of molecular aberrations. Y.-M.W., D.R.R., M.C., and A.M.C. developed the figures and tables. A.M.C., M.C., D.R.R., and Y.-M.W. wrote the manuscript with input from all authors. A.M.C. and M.T. designed and supervised the study.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Arul M. Chinnaiyan.

Reviewer Information Nature thanks S. Bova, P. Robbins and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Tables

    This file contains Supplementary Table 1 (Demographics and clinical details), Supplementary Table 2 (Sequencing statistics), Supplementary Table 4 (Pathogenic germline variants in the MET500 cohort), Supplementary Table 5 (Germline mutations in metastatic cancer), Supplementary Table 6 (Pathogenic fusions in the MET500 cohort) and Supplementary Table 7 (Immune cell infiltration analyses).

  2. 2.

    Reporting summary

Excel files

  1. 1.

    Supplementary Table 3

    This file contains Supplementary Table 3 (Recurrent molecular aberrations in the MET500 cohort).

About this article

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DOI

https://doi.org/10.1038/nature23306

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