Experimentally Derived Metastasis Gene Expression Profile Predicts Recurrence and Death in Patients With Colon Cancer
Background & aims
Staging inadequately predicts metastatic risk in patients with colon cancer. We used a gene expression profile derived from invasive, murine colon cancer cells that were highly metastatic in an immunocompetent mouse model to identify patients with colon cancer at risk of recurrence.
Methods
This phase 1, exploratory biomarker study used 55 patients with colorectal cancer from Vanderbilt Medical Center (VMC) as the training dataset and 177 patients from the Moffitt Cancer Center as the independent dataset. The metastasis-associated gene expression profile developed from the mouse model was refined with comparative functional genomics in the VMC gene expression profiles to identify a 34-gene classifier associated with high risk of metastasis and death from colon cancer. A metastasis score derived from the biologically based classifier was tested in the Moffitt dataset.
Results
A high score was significantly associated with increased risk of metastasis and death from colon cancer across all pathologic stages and specifically in stage II and stage III patients. The metastasis score was shown to independently predict risk of cancer recurrence and death in univariate and multivariate models. For example, among stage III patients, a high score translated to increased relative risk of cancer recurrence (hazard ratio, 4.7; 95% confidence interval, 1.566–14.05). Furthermore, the metastasis score identified patients with stage III disease whose 5-year recurrence-free survival was >88% and for whom adjuvant chemotherapy did not increase survival time.
Conclusion
A gene expression profile identified from an experimental model of colon cancer metastasis predicted cancer recurrence and death, independently of conventional measures, in patients with colon cancer.
Keywords: Gene Expression Profiling, Colon Cancer Prognosis, Predictive Gene Signature, Mouse Model
Abbreviations used in this paper: CTX, chemotherapy, DFS, disease-free survival, DSS, disease-specific survival, HR, hazard ratio, MCC, Moffitt Cancer Center, OS, overall survival, PH, proportional hazard, VMC, Vanderbilt Medical Center
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The current address for Fei Wu is Bureau of Communicable Disease and Prevention, Missouri Department of Health and Senior Services, 930 Wildwood, PO Box 570, Jefferson City, Missouri 65102. The current address for Carl Schmidt is The Ohio State University Medical Center, College of Medicine, Division of Surgical Oncology, N-924 Doan Hall, 410 West 10th Avenue, Columbus, OH 43210-1240.
GEO accession number is GSE17538. Complete Minimum information about a microarray experiment (MIAME)-compliant datasets for analysis is available (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE17538).
Conflicts of interest The authors disclose no conflicts.
Funding This work was supported by the following grants from the National Institutes of Health: CA69457, DK52334, CA068485, and CA077839 (R.D.B.); TL1 RR024978 and CA106183 (J.J.S.); CA46413, CA95103, and CA084239 (R.J.C.); CA112215 (T.J.Y.); and CA126588 and CA128323 (N.G.D.). Other sources of funding include the Society of University Surgeons-Ethicon Scholarship Award (J.J.S.).
J. Joshua Smith, Natasha G. Deane, Fei Wu, and R. Daniel Beauchamp contributed equally to this work.
PII: S0016-5085(09)01964-7
doi:10.1053/j.gastro.2009.11.005
© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
