title: Gene expression profiling identifies clinically relevant subtypes of prostate cancer.
abstract: Prostate cancer, a leading cause of cancer death, displays a broad range of clinical behavior from relatively indolent to aggressive metastatic disease. To explore potential molecular variation underlying this clinical heterogeneity, we profiled gene expression in 62 primary prostate tumors, as well as 41 normal prostate specimens and nine lymph node metastases, using cDNA microarrays containing approximately 26,000 genes. Unsupervised hierarchical clustering readily distinguished tumors from normal samples, and further identified three subclasses of prostate tumors based on distinct patterns of gene expression. High-grade and advanced stage tumors, as well as tumors associated with recurrence, were disproportionately represented among two of the three subtypes, one of which also included most lymph node metastases. To further characterize the clinical relevance of tumor subtypes, we evaluated as surrogate markers two genes differentially expressed among tumor subgroups by using immunohistochemistry on tissue microarrays representing an independent set of 225 prostate tumors. Positive staining for MUC1, a gene highly expressed in the subgroups with "aggressive" clinicopathological features, was associated with an elevated risk of recurrence (P = 0.003), whereas strong staining for AZGP1, a gene highly expressed in the other subgroup, was associated with a decreased risk of recurrence (P = 0.0008). In multivariate analysis, MUC1 and AZGP1 staining were strong predictors of tumor recurrence independent of tumor grade, stage, and preoperative prostate-specific antigen levels. Our results suggest that prostate tumors can be usefully classified according to their gene expression patterns, and these tumor subtypes may provide a basis for improved prognostication and treatment stratification.
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Jacques
authors.initials: J
authors.lastname: Lapointe
authors.forename: Chunde
authors.initials: C
authors.lastname: Li
authors.forename: John P
authors.initials: JP
authors.lastname: Higgins
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
authors.forename: Eric
authors.initials: E
authors.lastname: Bair
authors.forename: Kelli
authors.initials: K
authors.lastname: Montgomery
authors.forename: Michelle
authors.initials: M
authors.lastname: Ferrari
authors.forename: Lars
authors.initials: L
authors.lastname: Egevad
authors.forename: Walter
authors.initials: W
authors.lastname: Rayford
authors.forename: Ulf
authors.initials: U
authors.lastname: Bergerheim
authors.forename: Peter
authors.initials: P
authors.lastname: Ekman
authors.forename: Angelo M
authors.initials: AM
authors.lastname: DeMarzo
authors.forename: Robert
authors.initials: R
authors.lastname: Tibshirani
authors.forename: David
authors.initials: D
authors.lastname: Botstein
authors.forename: Patrick O
authors.initials: PO
authors.lastname: Brown
authors.forename: James D
authors.initials: JD
authors.lastname: Brooks
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Pollack
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D016022:Case-Control Studies; D020869:Gene Expression Profiling; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D018396:Mucin-1 / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D012008:Recurrence; D012307:Risk Factors; D029589:Seminal Plasma Proteins / Q000235:genetics; D000090203:Zn-Alpha-2-Glycoprotein
chemical_list: D014408:Biomarkers, Tumor; D018396:Mucin-1; D029589:Seminal Plasma Proteins; D000090203:Zn-Alpha-2-Glycoprotein