Tumor subtype defines distinct pathways of molecular and clinical progression in primary prostate cancer.

TitleTumor subtype defines distinct pathways of molecular and clinical progression in primary prostate cancer.
Publication TypeJournal Article
Year of Publication2021
AuthorsLiu D, Augello MA, Grbesa I, Prandi D, Liu Y, Shoag JE, R Karnes J, Trock BJ, Klein EA, Den RB, Demichelis F, Davicioni E, Sboner A, Barbieri CE
JournalJ Clin Invest
Date Published2021 05 17
KeywordsBiomarkers, Tumor, Databases, Nucleic Acid, Disease-Free Survival, Humans, Male, Middle Aged, Neoplasm Proteins, Prostatic Neoplasms, Registries, Retrospective Studies, RNA-Seq, Survival Rate

BACKGROUNDMolecular characterization of prostate cancer (PCa) has revealed distinct subclasses based on underlying genomic alterations occurring early in the natural history of the disease. However, how these early alterations influence subsequent molecular events and the course of the disease over its long natural history remains unclear.METHODSWe explored the molecular and clinical progression of different genomic subtypes of PCa using distinct tumor lineage models based on human genomic and transcriptomic data. We developed transcriptional classifiers, and defined "early" and "late" categories of molecular subclasses from 8,158 PCa patients. Molecular subclasses were correlated with clinical outcomes and pathologic characteristics using Kaplan-Meier and logistic regression analyses.RESULTSWe identified PTEN and CHD1 alterations as subtype-specific late progression events specifically in ERG-overexpressing (ERG+) and SPOP-mutant tumors, respectively, and 2 distinct progression models consisting of ERG/PTEN (normal to ERG+ to PTEN-deleted) and SPOP/CHD1 (normal to SPOP-mutated to CHD1-deleted) with shared early tumorigenesis but distinct pathways toward progression. We found that within ERG+ and SPOP-mutant subtypes, late events were associated with worse prognosis. Importantly, the clinical and pathologic features associated with distinct late events at radical prostatectomy were strikingly different; PTEN deletions were associated with increased locoregional stage, while CHD1 deletions were only associated with increased grade, despite equivalent metastatic potential.CONCLUSIONThese findings suggest a paradigm in which specific subtypes of PCa follow distinct pathways of progression, at both the molecular and clinical levels. Therefore, the interpretation of common clinical parameters such as locoregional tumor stage may be influenced by the underlying tumor lineage, and potentially influence management decisions.FUNDINGProstate Cancer Foundation, National Cancer Institute, Urology Care Foundation, Damon Runyon Cancer Research Foundation, US Department of Defense, and the AIRC Foundation.

Alternate JournalJ Clin Invest
PubMed ID33998599
PubMed Central IDPMC8121518
Grant ListP50 CA211024 / CA / NCI NIH HHS / United States
R01 CA233650 / CA / NCI NIH HHS / United States
R37 CA215040 / CA / NCI NIH HHS / United States
Related Faculty: 
Andrea Sboner, Ph.D.

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