Journal
CANCERS
Volume 12, Issue 1, Pages -Publisher
MDPI
DOI: 10.3390/cancers12010176
Keywords
prostate cancer; tumor classification; predictive biomarkers; gene signature; gene classifier
Categories
Funding
- Swiss National Science Foundation [310030-169942, IZLSZ3-170898, IZK0Z3-144637]
- Swiss Cancer League [KLS-3872-02-2016, KLS-4569-08-2018]
- Fondazione Fidinam
- Fondazione Ticinese per la Ricerca sul Cancro
- FEDER [PI18/00263, CB16/12/00228]
- [KFS3243-08-2013/Swiss Bridge]
- Swiss National Science Foundation (SNF) [310030_169942, IZK0Z3_144637, IZLSZ3_170898] Funding Source: Swiss National Science Foundation (SNF)
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In this study, we extracted prostate cell-specific gene sets (metagenes) to define the epithelial differentiation status of prostate cancers and, using a deconvolution-based strategy, interrogated thousands of primary and metastatic tumors in public gene profiling datasets. We identified a subgroup of primary prostate tumors with low luminal epithelial enrichment (LumE(low)). LumE(low) tumors were associated with higher Gleason score and mutational burden, reduced relapse-free and overall survival, and were more likely to progress to castration-resistant prostate cancer (CRPC). Using discriminant function analysis, we generate a predictive 10-gene classifier for clinical implementation. This mini-classifier predicted with high accuracy the luminal status in both primary tumors and CRPCs. Immunohistochemistry for COL4A1, a low-luminal marker, sustained the association of attenuated luminal phenotype with metastatic disease. We found also an association of LumE score with tumor phenotype in genetically engineered mouse models (GEMMs) of prostate cancer. Notably, the metagene approach led to the discovery of drugs that could revert the low luminal status in prostate cell lines and mouse models. This study describes a novel tool to dissect the intrinsic heterogeneity of prostate tumors and provide predictive information on clinical outcome and treatment response in experimental and clinical samples.
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