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Molecular Staging for Survival Prediction of Colorectal Cancer Patients

From the Departments of Surgery, Pathology, and Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; The Institute for Genomic Research, Rockville; Department of Statistics, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD; Department of Biochemistry, George Washington University, Washington, DC; The Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Skejby, Denmark; and Department of Medical Genetics, Biomedicum, Helsinki, Finland

Address reprint requests to Timothy J. Yeatman, MD, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, SRB-2, Tampa, FL 33612; email: yeatman{at}moffitt.usf.edu

PURPOSE: The Dukes' staging system is the gold standard for predicting colorectal cancer prognosis; however, accurate classification of intermediate-stage cases is problematic. We hypothesized that molecular fingerprints could provide more accurate staging and potentially assist in directing adjuvant therapy.

METHODS: A 32,000 cDNA microarray was used to evaluate 78 human colon cancer specimens, and these results were correlated with survival. Molecular classifiers were produced to predict outcome.

RESULTS: Molecular staging, based on 43 core genes, was 90% accurate (93% sensitivity, 84% specificity) in predicting 36-month overall survival in 78 patients. This result was significantly better than Dukes' staging (P = .03878), discriminated patients into significantly different groups by survival time (P < .001, log-rank test), and was significantly different from chance (P < .001, 1,000 permutations). Furthermore, the classifier was able to discriminate a survival difference in an independent test set from Denmark. Molecular staging identifies patient prognosis (as represented by 36-month survival) more accurately than the traditional clinical staging, particularly for intermediate Dukes' stage B and C patients. The classifier was based on a core set of 43 genes, including osteopontin and neuregulin, which have biologic significance for this disease.

CONCLUSION: These data support further evaluation of molecular staging to discriminate good from poor prognosis patients, with the potential to direct adjuvant therapy.

Supported by grants from the National Cancer Institute, Bethesda, MD; also supported by the Biostatistics Core and the Microarray Core at H. Lee Moffitt Cancer Center and services provided by the Research Computing Core, University of South Florida.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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