부산대학교 도서관

Keywords: castration-resistant; CRPC; genomics; heterogeneity; metastasis; multifocal; NEPC; pathology; prostate cancer; transcriptomics 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. Article Note: These authors contributed equally to the work. Conflict of interest statement: The University of Michigan and Harvard have a patent in the field of diagnostics and therapeutics for ETS gene fusion prostate cancer; ST, FD, and MAR are named as co-inventors. The diagnostic field of use was licensed to Hologic/Gen-Probe (who sublicensed some rights to Ventana/Roche) and is licensed to LynxDx. Cornell University has a patent on SPOP prostate cancer mutations in the field of diagnostics and therapeutics; MAR is a co-inventor. MAR serves on the Scientific Advisory Board of Neogenomics. ST is a co-inventor on a patent issued to Strata Oncology related to MSI determination and checkpoint inhibitor benefit. ST has the following other conflicts of interest: Employment (Strata Oncology); Leadership (Strata Oncology), Stock and Other Ownership Interests (Strata Oncology, Javelin Oncology); Consulting or Advisory Roles (Janssen, Astellas Medivation, Strata Oncology); Research Funding (Astellas Medivation); Travel, accommodation, and expenses (Strata Oncology, Genzyme). CAPTION(S): Figure S1. A summary of pathology features, phylogeny and clonality analyses for Patient 1 Figure S2. A summary of pathology features, phylogeny and clonality analyses for Patient 2 Figure S3. A summary of pathology features, phylogeny and clonality analyses for Patient 3 Figure S4. A summary of pathology features, phylogeny and clonality analyses for Patient 4 Figure S5. A summary of pathology features, phylogeny and clonality analyses for Patient 5 Figure S6. A summary of pathology features, phylogeny and clonality analyses for Patient 7 Figure S7. A summary of pathology features, phylogeny and clonality analyses for Patient 8 Figure S8. A summary of pathology features, phylogeny and clonality analyses for Patient 10 Figure S9. Patient 6, primary tumor focus T4 Table S1. Sample summary: A summary of samples for each patient, together with pathology findings and interpretation of clonality based on pathology and on genomics Table S2. Treatments: A summary of the therapies received by each patient before metastatic biopsy, when available Table S3. WES SNV-clonality: A list of WES-based SNV calls per sample, as used for phylogeny and clonality analyses (after applying additional filters described in Materials and methods) Table S4. WES indels: A list of WES-based short insertions and deletions per sample Table S5. WES CNA: A list of WES-based copy number alterations (CNA) by CLONET Table S6. AmpliSeq SNV: A list of targeted sequencing-based SNV and indel calls per sample Table S7. AmpliSeq CNA: A list of targeted sequencing-based CNA calls per sample Byline: Joanna Cyrta, Davide Prandi, Arshi Arora, Daniel H Hovelson, Andrea Sboner, Antonio Rodriguez, Tarcisio Fedrizzi, Himisha Beltran, Dan R Robinson, Anuradha Gopalan, Lawrence True, Peter S Nelson, Brian D Robinson, Juan Miguel Mosquera, Scott A Tomlins, Ronglai Shen, Francesca Demichelis, Mark A Rubin