Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival
- Howard Y. Changa,b,c,
- Dimitry S. A. Nuytenc,d,e,
- Julie B. Sneddonb,
- Trevor Hastief,
- Robert Tibshiranif,
- Therese Sørlieb,g,
- Hongyue Daih,i,
- Yudong D. Heh,i,
- Laura J. van't Veerd,i,
- Harry Bartelinke,
- Matt van de Rijnj,
- Patrick O. Brownb,k,l, and
- Marc J. van de Vijverd,l
- aProgram in Epithelial Biology, Departments of bBiochemistry, fHealth Research and Policy, and jPathology, and kHoward Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; Departments of dDiagnostic Oncology and eRadiation Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; hRosetta Inpharmatics, Seattle, WA 98109; and gNorwegian Radium Hospital, 0310 Oslo, Norway
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Contributed by Patrick O. Brown, January 5, 2005
Abstract
Based on the hypothesis that features of the molecular program of normal wound healing might play an important role in cancer metastasis, we previously identified consistent features in the transcriptional response of normal fibroblasts to serum, and used this “wound-response signature” to reveal links between wound healing and cancer progression in a variety of common epithelial tumors. Here, in a consecutive series of 295 early breast cancer patients, we show that both overall survival and distant metastasis-free survival are markedly diminished in patients whose tumors expressed this wound-response signature compared to tumors that did not express this signature. A gene expression centroid of the wound-response signature provides a basis for prospectively assigning a prognostic score that can be scaled to suit different clinical purposes. The wound-response signature improves risk stratification independently of known clinico-pathologic risk factors and previously established prognostic signatures based on unsupervised hierarchical clustering (“molecular subtypes”) or supervised predictors of metastasis (“70-gene prognosis signature”).
Footnotes
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↵ l To whom correspondence may be addressed. E-mail: m.vd.vijver{at}nki.nl or pbrown{at}cmgm.stanford.edu.
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↵ c H.Y.C. and D.S.A.N. contributed equally to this work.
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↵ i L.J.V. holds equity in Agendia, which has commercial interests in the 70-gene prognosis signature. H.D. and Y.D.H. hold shares of Merck.
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Author contributions: H.Y.C., D.S.A.N., M.v.d.R., and P.O.B. designed research; H.Y.C., D.S.A.N., and T.H. performed research; H.Y.C., D.S.A.N., T.H., J.B.S., H.D., Y.H., and L.J.v.t.V. contributed new reagents/analytic tools; H.Y.C., D.S.A.N., T.H., R.T., J.B.S., T.S., H.B., M.J.v.d.V., and P.O.B. analyzed data; and H.Y.C., D.S.A.N., H.B., M.J.v.d.V., and P.O.B. wrote the paper.
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Abbreviations: CSR, core serum response; DMFP, distant metastasis-free probability; NIH, National Institutes of Health.
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See Commentary on page 3531.
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Freely available online through the PNAS open access option.
- Copyright © 2005, The National Academy of Sciences
