Comparative genomics of primary prostate cancer and paired metastases: insights from 12 molecular case studies.

Cyrta, Joanna; Prandi, Davide; Arora, Arshi; Hovelson, Daniel H; Sboner, Andrea; Rodriguez, Antonio; Fedrizzi, Tarcisio; Beltran, Himisha; Robinson, Dan R; Gopalan, Anurandha; True, Lawrence; Nelson, Peter S; Robinson, Brian D; Mosquera, Juan Miguel; Tomlins, Scott A; Shen, Ronglai; Demichelis, Francesca; Rubin, Mark A (2022). Comparative genomics of primary prostate cancer and paired metastases: insights from 12 molecular case studies. The journal of pathology, 257(3), pp. 274-284. Wiley 10.1002/path.5887

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie

04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Cyrta, Joanna; Rodríguez Calero, José Antonio and Rubin, Mark Andrew

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1096-9896

Publisher:

Wiley

Language:

English

Submitter:

Pubmed Import

Date Deposited:

01 Mar 2022 10:26

Last Modified:

04 Jun 2022 00:13

Publisher DOI:

10.1002/path.5887

PubMed ID:

35220606

Uncontrolled Keywords:

CRPC NEPC castration-resistant genomics heterogeneity metastasis multifocal pathology prostate cancer transcriptomics

BORIS DOI:

10.48350/166225

URI:

https://boris.unibe.ch/id/eprint/166225

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