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 Ϸ26,000 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.

MUC-1 gene is associated with prostate cancer death: a 20-year follow-up of a population-based study in Sweden

“…Differences in the assessment of MUC-1 expression may explain the diverging results however; although we evaluated staining intensity, Kirchenbaum et al examined staining patterns (apical and diffuse). Our data furthermore confirm the results of Lapointe et al (2004) demonstrating that MUC-1 is an independent prognostic marker that adds prognostic information over and above known risk factors of grade and stage.…”

“…In prostate cancer, overexpression of MUC-1 in tissue has been correlated both with higher Gleason grade and advanced tumour stage (Kirschenbaum et al, 1999). One study has, furthermore, suggested that MUC-1 expression may predict prostate cancer recurrence after prostatectomy (Lapointe et al, 2004), although these results have been challenged by others (O'Connor et al, 2005;Zellweger et al, 2005).…”

A variant TMPRSS2 isoform and ERG fusion product in prostate cancer with implications for molecular diagnosis

“…11 Briefly, 54 freshly frozen primary prostate tumor specimens (obtained from radical prostatectomy) and nine therapy-naive metastatic pelvic lymph node specimens (from aborted surgery) were scalpel-dissected such that Z50% of cells were epithelial, and Z90% of epithelial cells were neoplastic. Total RNA was extracted using the Trizol (Invitrogen, Carlsbad, CA, USA) method.…”

Comparative and integrative functional genomics of HCC

“…Gene expression profiling studies of various cancers have discovered consistent gene expression patterns associated with a histological or clinical phenotype and discovering subtypes of cancers previously unidentified with conventional technologies (Alizadeh et al, 2000;van de Vijver et al, 2002;Bullinger et al, 2004;Dave et al, 2004;Lapointe et al, 2004;Valk et al, 2004;Lee et al, 2004a;Roepman et al, 2005). This approach promises to provide diagnostic and prognostic markers that can be clinically used in the near future (Lossos et al, 2004).…”