Molecular profiling of prostatic acinar morphogenesis identifies PDCD4 and KLF6 as tissue architecture-specific prognostic markers in prostate cancer.

TitleMolecular profiling of prostatic acinar morphogenesis identifies PDCD4 and KLF6 as tissue architecture-specific prognostic markers in prostate cancer.
Publication TypeJournal Article
Year of Publication2013
AuthorsLi C-R, Su JJ-M, Wang W-Y, Lee MT-L, Wang T-Y, Jiang K-Y, Li C-F, Hsu J-M, Chen C-K, Chen M, Jiang S-S, Weaver VM, Tsai KK-C
JournalAm J Pathol
Volume182
Issue2
Pagination363-74
Date Published2013 Feb
ISSN1525-2191
KeywordsAcinar Cells, Aged, Apoptosis Regulatory Proteins, Cell Differentiation, Epithelial Cells, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Kruppel-Like Transcription Factors, Male, Middle Aged, Morphogenesis, Organ Specificity, Prognosis, Prostate, Prostatic Neoplasms, Proto-Oncogene Proteins, Recurrence, RNA-Binding Proteins, Tumor Markers, Biological
Abstract

Histopathological classification of human prostate cancer (PCA) relies on the morphological assessment of tissue specimens but has limited prognostic value. To address this deficiency, we performed comparative transcriptome analysis of human prostatic acini generated in a three-dimensional basement membrane that recapitulates the differentiated morphological characteristics and gene expression profile of a human prostate glandular epithelial tissue. We then applied an acinar morphogenesis-specific gene profile to two independent cohorts of patients with PCA (total n = 79) and found that those with tumors expressing this profile, which we designated acini-like tumors, had a significantly lower risk of postoperative relapse compared with those tumors with a lower correlation (hazard ratio, 0.078; log-rank test P = 0.009). Multivariate analyses showed superior prognostic prediction performance using this classification system compared with clinical criteria and Gleason scores. We prioritized the genes in this profile and identified programmed cell death protein 4 (PDCD4) and Kruppel-like factor 6 (KLF6) as critical regulators and surrogate markers of prostatic tissue architectures, which form a gene signature that robustly predicts clinical prognosis with a remarkable accuracy in several large series of PCA tumors (total n = 161; concordance index, 0.913 to 0.951). Thus, by exploiting the genomic program associated with prostate glandular differentiation, we identified acini-like PCA and related molecular markers that significantly enhance prognostic prediction of human PCA.

DOI10.1016/j.ajpath.2012.10.024
Alternate JournalAm. J. Pathol.
PubMed ID23219426
PubMed Central IDPMC3562735
Grant ListP50 CA 58207 / CA / NCI NIH HHS / United States
P50 CA058207 / CA / NCI NIH HHS / United States
R01 CA138818 / CA / NCI NIH HHS / United States
R01 CA140663 / CA / NCI NIH HHS / United States
R01 CA140663-01A2 / CA / NCI NIH HHS / United States