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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hellman, S., DeVita, V.T. & Rosenberg, S.A. Cancer: principles & practice of oncology. (Lippincott-Raven, Philadelphia, 2001).
Poste, G. & Fidler, I.J. The pathogenesis of cancer metastasis. Nature 283, 139–146 (1980).
Fidler, I.J. & Kripke, M.L. Metastasis results from pre-existing variant cells within a malignant tumor. Science 197, 893–895 (1977).
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).
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).
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).
van't Veer, L.J. et al. Gene-expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).
Singh, D. et al. Gene expression correlates of clinical prostate cancer behavior. Cancer Cell 1, 203–209 (2002).
Pomeroy, S.L. et al. Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415, 436–442 (2002).
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).
Anand, N. et al. Protein elongation factor EEF1A2 is a putative oncogene in ovarian cancer. Nat. Genet. 31, 301–305 (2002).
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).
Jallepalli, P.V. et al. Securin is required for chromosomal stability in human cells. Cell 105, 445–457 (2001).
Heaney, A.P. et al. Expression of pituitary-tumour transforming gene in colorectal tumours. Lancet 355, 716–719 (2000).
Bernal, J.A. et al. Human securin interacts with p53 and modulates p53-mediated transcriptional activity and apoptosis. Nat. Genet. 32, 306–311 (2002).
Skobe, M. & Fusenig, N.E. Tumorigenic conversion of immortal human keratinocytes through stromal cell activation. Proc. Natl. Acad. Sci. USA 95, 1050–1055 (1998).
Olumi, A.F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).
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).
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).
Pardoll, D.M. Spinning molecular immunology into successful immunotherapy. Nat. Rev. Immunol. 2, 227–238 (2002).
Song, W.J. et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat. Genet. 23, 166–175 (1999).
Bernards, R. & Weinberg, R.A. Metastasis genes: a progression puzzle. Nature 418, 823 (2002).
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).
Hainsworth, J.D. & Greco, F.A. Treatment of patients with cancer of an unknown primary site. N. Engl. J. Med. 329, 257–263 (1993).
Perou, C.M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).
Alizadeh, A.A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene-expression profiling. Nature 403, 503–511 (2000).
Ramaswamy, S. et al. Multiclass cancer diagnosis using tumor gene-expression signatures. Proc. Natl. Acad. Sci. USA 98, 15149–15154 (2001).
Golub, T.R. et al. Molecular classification of cancer: class discovery and class prediction by gene-expression monitoring. Science 286, 531–537 (1999).
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).
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.
The authors declare no competing financial interests.
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.
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). https://doi.org/10.1038/ng1060
Multi-omics characterization and validation of invasiveness-related molecular features across multiple cancer types
Journal of Translational Medicine (2021)
Journal of Experimental & Clinical Cancer Research (2021)
Surgical and Experimental Pathology (2021)
Clinical Reviews in Allergy & Immunology (2021)