Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

You are viewing this page in draft mode.

A molecular signature of metastasis in primary solid tumors


Metastasis is the principal event leading to death in individuals with cancer, yet its molecular basis is poorly understood1. To explore the molecular differences between human primary tumors and metastases, we compared the gene-expression profiles of adenocarcinoma metastases of multiple tumor types to unmatched primary adenocarcinomas. We found a gene-expression signature that distinguished primary from metastatic adenocarcinomas. More notably, we found that a subset of primary tumors resembled metastatic tumors with respect to this gene-expression signature. We confirmed this finding by applying the expression signature to data on 279 primary solid tumors of diverse types. We found that solid tumors carrying the gene-expression signature were most likely to be associated with metastasis and poor clinical outcome (P < 0.03). These results suggest that the metastatic potential of human tumors is encoded in the bulk of a primary tumor, thus challenging the notion that metastases arise from rare cells within a primary tumor that have the ability to metastasize2.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Genes associated with metastases.
Figure 2: Hierarchical clustering and Kaplan–Meier survival analysis in lung adenocarcinoma.
Figure 3: Broad diagnostic utility of the signature associated with metastasis in solid tumors.


  1. 1

    Hellman, S., DeVita, V.T. & Rosenberg, S.A. Cancer: principles & practice of oncology. (Lippincott-Raven, Philadelphia, 2001).

    Google Scholar 

  2. 2

    Poste, G. & Fidler, I.J. The pathogenesis of cancer metastasis. Nature 283, 139–146 (1980).

    CAS  Article  Google Scholar 

  3. 3

    Fidler, I.J. & Kripke, M.L. Metastasis results from pre-existing variant cells within a malignant tumor. Science 197, 893–895 (1977).

    CAS  Article  Google Scholar 

  4. 4

    Clark, E.A., Golub, T.R., Lander, E.S. & Hynes, R.O. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406, 532–535 (2000).

    CAS  Article  Google Scholar 

  5. 5

    Bhattacharjee, A. et al. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc. Natl. Acad. Sci. USA 98, 13790–13795 (2001).

    CAS  Article  Google Scholar 

  6. 6

    Schiller, J.H. et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N. Engl. J. Med. 346, 92–98 (2002).

    CAS  Article  Google Scholar 

  7. 7

    van't Veer, L.J. et al. Gene-expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).

    CAS  Article  Google Scholar 

  8. 8

    Singh, D. et al. Gene expression correlates of clinical prostate cancer behavior. Cancer Cell 1, 203–209 (2002).

    CAS  Article  Google Scholar 

  9. 9

    Pomeroy, S.L. et al. Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415, 436–442 (2002).

    CAS  Article  Google Scholar 

  10. 10

    Shipp, M.A. et al. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat. Med. 8, 68–74 (2002).

    CAS  Article  Google Scholar 

  11. 11

    Anand, N. et al. Protein elongation factor EEF1A2 is a putative oncogene in ovarian cancer. Nat. Genet. 31, 301–305 (2002).

    CAS  Article  Google Scholar 

  12. 12

    Zou, H., McGarry, T.J., Bernal, T. & Kirschner, M.W. Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis. Science 285, 418–422 (1999).

    CAS  Article  Google Scholar 

  13. 13

    Jallepalli, P.V. et al. Securin is required for chromosomal stability in human cells. Cell 105, 445–457 (2001).

    CAS  Article  Google Scholar 

  14. 14

    Heaney, A.P. et al. Expression of pituitary-tumour transforming gene in colorectal tumours. Lancet 355, 716–719 (2000).

    CAS  Article  Google Scholar 

  15. 15

    Bernal, J.A. et al. Human securin interacts with p53 and modulates p53-mediated transcriptional activity and apoptosis. Nat. Genet. 32, 306–311 (2002).

    CAS  Article  Google Scholar 

  16. 16

    Skobe, M. & Fusenig, N.E. Tumorigenic conversion of immortal human keratinocytes through stromal cell activation. Proc. Natl. Acad. Sci. USA 95, 1050–1055 (1998).

    CAS  Article  Google Scholar 

  17. 17

    Olumi, A.F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Brown, L.F. et al. Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast. Clin. Cancer Res. 5, 1041–1056 (1999).

    CAS  PubMed  Google Scholar 

  19. 19

    Jensen, B.V., Johansen, J.S., Skovsgaard, T., Brandt, J. & Teisner, B. Extracellular matrix building marked by the N-terminal propeptide of procollagen type I reflect aggressiveness of recurrent breast cancer. Int. J. Cancer 98, 582–589 (2002).

    CAS  Article  Google Scholar 

  20. 20

    Pardoll, D.M. Spinning molecular immunology into successful immunotherapy. Nat. Rev. Immunol. 2, 227–238 (2002).

    CAS  Article  Google Scholar 

  21. 21

    Song, W.J. et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat. Genet. 23, 166–175 (1999).

    CAS  Article  Google Scholar 

  22. 22

    Bernards, R. & Weinberg, R.A. Metastasis genes: a progression puzzle. Nature 418, 823 (2002).

  23. 23

    Braun, S. et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N. Engl. J. Med. 342, 525–533 (2000).

    CAS  Article  Google Scholar 

  24. 24

    Hainsworth, J.D. & Greco, F.A. Treatment of patients with cancer of an unknown primary site. N. Engl. J. Med. 329, 257–263 (1993).

    CAS  Article  Google Scholar 

  25. 25

    Perou, C.M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).

    CAS  Article  Google Scholar 

  26. 26

    Alizadeh, A.A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene-expression profiling. Nature 403, 503–511 (2000).

    CAS  Article  Google Scholar 

  27. 27

    Ramaswamy, S. et al. Multiclass cancer diagnosis using tumor gene-expression signatures. Proc. Natl. Acad. Sci. USA 98, 15149–15154 (2001).

    CAS  Article  Google Scholar 

  28. 28

    Golub, T.R. et al. Molecular classification of cancer: class discovery and class prediction by gene-expression monitoring. Science 286, 531–537 (1999).

    CAS  Article  Google Scholar 

  29. 29

    Eisen, M.B., Spellman, P.T., Brown, P.O. & Botstein, D. Cluster analysis and display of genome-wide expression patterns. Proc. Natl. Acad. Sci. USA 95, 14863–14868 (1998).

    CAS  Article  Google Scholar 

Download references


We thank R. A. Weinberg, P. Tamayo and M. A. Gillette for helpful comments. This work was supported in part by a grant from the US National Institutes of Health to T.R.G.

Author information



Corresponding authors

Correspondence to Sridhar Ramaswamy or Todd R. Golub.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Web Note A

Technical Note:

Web Table A  This is a compressed .ZIP file containing 2 individual files. These files include an Excel file containing supplementary data (Web Table A) and a pdf file containing a guide to Web Table A (Guide To Web Table A). Simply click on the link to download the compressed file. Then ... PC Users: You can open this file using WinZip software (if you don't already have WinZip, click on the "Download Plugins" link on the left nav bar). Once you have unzipped the compressed file, you can choose to extract the individual files. Mac Users: You can open this file using StuffIt software (if you don't already have StuffIt, click on the "Download Plugins" link on the left nav bar). Once you have unzipped the compressed file, you can choose to extract the individual files.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ramaswamy, S., Ross, K., Lander, E. et al. A molecular signature of metastasis in primary solid tumors. Nat Genet 33, 49–54 (2003).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing