Comparative genomics of primary prostate cancer and paired metastases: insights from 12 molecular case studies. Issue 3 (28th March 2022)

• Record Type: Journal Article
• Authors: Cyrta, Joanna; Prandi, Davide; Arora, Arshi; Hovelson, Daniel H; Sboner, Andrea; Rodriguez, Antonio; Fedrizzi, Tarcisio; Beltran, Himisha; Robinson, Dan R; Gopalan, Anuradha; True, Lawrence; Nelson, Peter S; Robinson, Brian D; Mosquera, Juan Miguel; Tomlins, Scott A; Shen, Ronglai; Demichelis, Francesca; Rubin, Mark A
• Is Part Of: Journal of pathology. Volume 257:Issue 3(2022)
• Page Start: 274
• Page End: 284
• Publication Date: 2022-03-28
• Subjects: castration‐resistant -- CRPC -- genomics -- heterogeneity -- metastasis -- multifocal -- NEPC -- pathology -- prostate cancer -- transcriptomics; Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.5887
• Languages: English
• ISSNs: 0022-3417

Abstract

Abstract: 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 the 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 intratumor 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. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.