BACKGROUND. Molecular 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. METHODS. We 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. RESULTS. We 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. CONCLUSION. These 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. FUNDING. Prostate Cancer Foundation, National Cancer Institute, Urology Care Foundation, Damon Runyon Cancer Research Foundation, US Department of Defense, and the AIRC Foundation.
|Journal||Journal of Clinical Investigation|
|State||Published - May 2021|
Bibliographical noteFunding Information:
Authorship note: AS and CEB jointly supervised this work. Conflict of interest: YL reports employment with Decipher Biosciences. RJK reports patents, royalties, and other intellectual property with Decipher Biosciences. BJT reports consulting or advisory roles with Decipher Biosciences and Myriad Genetics, and research funding from Myriad Genetics and MDxHealth. EAK reports consulting or advisory roles with Decipher Biosciences and Genomic Health, and is a member of the Speakers’ Bureau for Genomic Health. RBD reports a consulting or advisory role for Decipher Biosciences, is a member of the Speakers’ Bureau for Bayer, and reports research funding from Medivation, Astellas Pharma, and Decipher Biosciences, and travel, accommodations, and expense reimbursement from Decipher Biosciences. ED reports employment, holding a leadership position, stock and other ownership interests, and travel, accommodations, and expense reimbursement from Decipher Biosciences, as well as a patent: Cancer diagnostics using biomarkers (patent 20140066323). CEB is a coinventor on a patent application filed regarding SPOP mutations in prostate cancer by Weill Cornell Medicine. Copyright: © 2021, American Society for Clinical Investigation. Submitted: March 30, 2021; Accepted: April 7, 2021; Published: May 17, 2021. Reference information: J Clin Invest. 2021;131(10):e147878. https://doi.org/10.1172/JCI147878.Submitted: January 19, 2021; Accepted: April 7, 2021; Published: May 17, 2021.
We are grateful to the prostate cancer patients and families who contributed to this research. We thank The Cancer Genome Atlas Research Network (TCGA) for providing the prostate cancer genomic and transcriptomic data. We thank the Weill Cornell Medicine Genomics and Epigenomics Core Facility and the MSKCC cBioPortal. This work was supported by the Prostate Cancer Foundation (to CEB, DL, and MAA), NCI (P50CA211024 and R01CA233650 to CEB), a Urology Care Foundation Rising Star in Urology Research Award (to CEB), Damon Runyon Cancer Research Foundation MetLife Foundation Family Clinical Investigator Award (to CEB), US Department of Defense Postdoctoral Fellowship (W81XWH-17-1-0137 to MAA), and Foundation AIRC (IG 19221 to FD).
© 2021, American Society for Clinical Investigation.