Molecular Profiling of Prostatic Acinar Morphogenesis Identifies PDCD4 and KLF6 as Tissue Architecture–Specific Prognostic Markers in Prostate Cancer

• DOI: 10.1016/j.ajpath.2012.10.024
• Publication Date: 2012-12-04T21:45:17Z
• Authors: Chi-Rong Li; Jimmy J.-M. Su; Wei-Yu Wang; Michael T.-L. Lee; Ting-Yun Wang; Kuan-Ying Jiang; Chein-Feng Li; Jong-Ming Hsu; Chi-Kuan Chen; Marcelo Chen; Shih-Sheng Jiang; Valerie M. Weaver; Kelvin K.-C. Tsai
• Keywords: Urologic Diseases; Male; 0301 basic medicine; Aging; Biomedical and clinical sciences; Clinical Sciences; Oncology and Carcinogenesis; Kruppel-Like Transcription Factors; 610; Acinar Cells; Medical and Health Sciences; Pathology and Forensic Medicine; 03 medical and health sciences; Cancer Genomics; Recurrence; Proto-Oncogene Proteins; Genetics; Pathology; Biomarkers, Tumor; Kruppel-Like Factor 6; Morphogenesis; Humans; Cancer; Aged; Neoplastic; 0303 health sciences; Tumor; Biomedical and Clinical Sciences; Prostate Cancer; Prevention; Gene Expression Profiling; Human Genome; Prostate; Health sciences; Prostatic Neoplasms; RNA-Binding Proteins; Cell Differentiation; Epithelial Cells; Middle Aged; Prognosis; 4.1 Discovery and preclinical testing of markers and technologies; 3. Good health; Gene Expression Regulation, Neoplastic; Gene Expression Regulation; Organ Specificity; Apoptosis Regulatory Proteins; Biomarkers

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.