Primary prostate cancer (PCa) can show marked molecular heterogeneity. However, systematic analyses comparing primary PCa and matched metastases in individual patients are lacking. We aimed to address the molecular aspects of metastatic progression while accounting for heterogeneity of primary PCa. In this pilot study, we collected 12 radical prostatectomy (RP) specimens from men who subsequently developed metastatic castration-resistant prostate cancer (mCRPC). We used histomorphology (Gleason grade, focus size, stage) and immunohistochemistry (IHC) (ERG and p53) to identify independent tumors and/or distinct subclones of primary PCa. We then compared molecular profiles of these primary PCa areas to matched metastatic samples using whole exome sequencing (WES) and amplicon-based DNA and RNA sequencing. Based on combined pathology and molecular analysis, seven (58%) RP specimens harbored monoclonal and topographically continuous disease, albeit with some degree of intra-tumor heterogeneity; four (33%) specimens showed true multifocal disease; and one displayed monoclonal disease with discontinuous topography. Early (truncal) events in primary PCa included SPOP p.F133V (one patient), BRAF p.K601E (one patient), and TMPRSS2:ETS rearrangements (eight patients). Activating AR alterations were seen in nine (75%) mCRPC patients, but not in matched primary PCa. Hotspot TP53 mutations, found in metastases from three patients, were readily present in matched primary disease. Alterations in genes encoding epigenetic modifiers were observed in several patients (either shared between primary foci and metastases or in metastatic samples only). WES-based phylogenetic reconstruction and/or clonality scores were consistent with the index focus designated by pathology review in six out of nine (67%) cases. The three instances of discordance pertained to monoclonal, topographically continuous tumors, which would have been considered as unique disease in routine practice. Overall, our results emphasize pathologic and molecular heterogeneity of primary PCa, and suggest that comprehensive IHC-assisted pathology review and genomic analysis are highly concordant in nominating the 'index' primary PCa area. This article is protected by copyright. All rights reserved.
The Journal of pathology. 2022 Feb 26 [Epub ahead of print]
Joanna Cyrta, Davide Prandi, Arshi Arora, Daniel H Hovelson, Andrea Sboner, Antonio Rodriguez, Tarcisio Fedrizzi, Himisha Beltran, Dan R Robinson, Anurandha Gopalan, Lawrence True, Peter S Nelson, Brian D Robinson, Juan Miguel Mosquera, Scott A Tomlins, Ronglai Shen, Francesca Demichelis, Mark A Rubin
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA., Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy., Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA., Center for Computational Medicine and Bioinformatics, Univ. Michigan, Ann Arbor, MA, USA., Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA., Department for BioMedical Research, University of Bern, Bern, Switzerland., Department of Medicine, Division of Medical Oncology, Weill Cornell Medicine, New York, NY, USA., Department of Pathology, University of Michigan, Ann Arbor, MI, USA., Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Pathology, Univ. of Washington, Seattle, WA, USA., Fred Hutchinson Cancer Research Center, Seattle, WA, USA.