The prognosis of men with moderate-grade prostate cancer is uncertain. At present, there are few if any reliable molecular markers that can distinguish moderate-grade tumors from those that behave more aggressively. To better understand the molecular basis of human prostate cancer and potentially provide information toward more accurate prognosis, we measured and analyzed gene expression profiles of 13 high- and moderate-grade human prostate tumors using cDNA microarrays. The expression of 136 genes was observed to differ significantly (P < 0.001) between normal prostate and tumors using one-sample t testing and Wilcoxon ranking. Hierarchical clustering of genes demonstrated a relatively similar pattern of differential expression across the tumors. However, importantly, permutation t tests (two-tailed P < 0.001) revealed 21 genes whose expression profiles segregated moderate- and high-grade tumors from each other, which was significantly (P < 0.03) greater than what was expected by chance. These results were compared in silico with prostate cancer profiling efforts performed by other groups, including a meta-analysis of four data sets, which validated many of the dysregulated genes. We suggest that these data provide insight into the molecular nature of clinically aggressive prostate cancer.
Carcinoma of the prostate is the most common neoplasm and second leading cause of cancer death in men in the Western world (1). The majority of men diagnosed with the disease have moderate-grade tumors with an uncertain prognosis. Most of these men will do well; however, a significant percentage of these tumors will behave as though they were high-grade, with relatively rapid metastasis and high mortality. Recent efforts using high-throughput gene expression technology are beginning to delineate the molecular alterations associated with prostate tumor initiation and progression (2–8). In addition to providing a mechanistic understanding of prostate carcinogenesis at a molecular level, mRNA expression measurements may have immediate clinical utility. At present, there are few known genes (or patterns of genes) whose expression levels can distinguish moderate-from high-grade cancers. Identifying such marker genes would augment the accuracy and significance of diagnosis provided by the currently used grading system based on histologic architecture (8). In an attempt to increase our basic understanding of prostate tumorigenesis, as well as to search for clinically useful markers of aggressive cancer, we performed global gene expression analysis of prostate tumors using a 6400-element cDNA microarray. Furthermore, a recent meta-analysis of four independent studies of gene expression profiles of prostate cancer provided for interstudy validation of dysregulated genes, including the identification of several affected pathways (9). This approach highlights the importance of multi-institutional efforts in prostate cancer gene expression profiling for cross-study validation.
From the Pathogenetics Unit, Laboratory of Pathology and Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD (C.J.M.B., I.M.L., R.F.C., J.W.G., P.H.D., M.M., W.M.L., M.E.B); Pontificia Universidad Catolica de Chile, Santiago (I.M.L.); Science Applications International Corporation, National Cancer Institute (J.W.G.); Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute (Y.Z., R.S.); Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute (J.J.K., J.E.G.); and Mayo Clinic, Rochester, MI, and Bostwick Laboratories, Richmond, VA (D.G.B.).
Address correspondence and reprint requests to Dr. Michael R. Emmert-Buck, Laboratory of Pathology, Building 10, Room 2A33, 10 Center Drive, Bethesda, MD 20892 (e-mail: firstname.lastname@example.org).