Molecular Profiling of Prostatic Acinar Morphogenesis Identifies PDCD4 and KLF6 as Tissue Architecture–Specific Prognostic Markers in Prostate Cancer
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
DOI:
10.1016/j.ajpath.2012.10.024
Publication Date:
2012-12-04T21:45:17Z
AUTHORS (13)
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.
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CITATIONS (12)
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