Integrated Classification of Prostate Cancer Reveals a Novel Luminal Subtype with Poor Outcome

Abstract

Prostate cancer (PC) is a biologically heterogeneous disease with variable molecular alterations underlying cancer initiation and progression. Despite recent advances in understanding PC heterogeneity, better methods for classification of PC are still needed to improve prognostic accuracy and therapeutic outcomes. In this study we computationally assembled a large virtual cohort (n=1,321) of human PC transcriptome profiles from 38 distinct cohorts and, using pathway activation signatures of known relevance to PC, developed a novel classification system consisting of 3 distinct subtypes (named PCS1 to 3). We validated this subtyping scheme in 10 independent patient cohorts and 19 laboratory models of PC, including cell lines and genetically engineered mouse models. Analysis of subtype-specific gene expression patterns in independent datasets derived from luminal and basal cell models provides evidence that PCS1 and PCS2 tumors reflect luminal subtypes, while PCS3 represents a basal subtype. We show that PCS1 tumors progress more rapidly to metastatic disease in comparison to PCS2 or PCS3, including PSC1 tumors of low Gleason grade. To apply this finding clinically, we developed a 37-gene panel that accurately assigns individual tumors to one of the 3 PCS subtypes. This panel was also applied to circulating tumor cells (CTCs) and provided evidence that PCS1 CTCs may reflect enzalutamide resistance. In summary, PCS subtyping may improve accuracy in predicting the likelihood of clinical progression and permit treatment stratification at early and late disease stages.

Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor

“…Importantly, we here demonstrate that morphological characteristics of bone metastasis subtypes can be traced back to their corresponding primary tumors (see below). In line with this, the MetA, MetB, and MetC subtypes show phenotypic characteristics resembling those previously described for molecular subtypes of primary prostate tumors: the PC subtypes 2, 1, and 3 (You et al ., ) and the luminal A, luminal B, and basal subtypes as determined by the PAM50 breast cancer panel (Zhao et al ., ), respectively. Taken together, this may suggest that the primary tumor subtype could be maintained in bone metastases.…”

TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup

“…Genetic pathways and/or gene expression panels to predict PCa outcome and response to therapeutic interventions (35) are promising. Three recent gene expression panels have reported success in predicting PCa patient outcome, in terms of BCR, mortality, and metastatic progression (36–40). While these panels have indicated patient outcomes, they have yet to provide and/or validate targeted therapy approaches that could intercept a patient’s progression to metastatic disease.…”

Comprehensive palmitoyl-proteomic analysis identifies distinct protein signatures for large and small cancer-derived extracellular vesicles

“…Differentially expressed proteins among groups were selected based on an averaged relative expression difference >0.1 and a p-value<0.05 by one-sample t-test. Transcriptional information was recovered from the Prostate Cancer Transcriptome Atlas (PCTA; www.thepcta.org) 40 and The Cancer Genome Atlas (TCGA, https://portal.gdc.cancer.gov) 41 databases.…”