Dataset Information

Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

ABSTRACT: Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.

SUBMITTER: Cooper CS

PROVIDER: S-EPMC4380509 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

Cooper Colin S CS Eeles Rosalind R Wedge David C DC Van Loo Peter P Gundem Gunes G Alexandrov Ludmil B LB Kremeyer Barbara B Butler Adam A Lynch Andrew G AG Camacho Niedzica N Massie Charlie E CE Kay Jonathan J Luxton Hayley J HJ Edwards Sandra S Kote-Jarai ZSofia Z Dennis Nening N Merson Sue S Leongamornlert Daniel D Zamora Jorge J Corbishley Cathy C Thomas Sarah S Nik-Zainal Serena S O'Meara Sarah S Matthews Lucy L Clark Jeremy J Hurst Rachel R Mithen Richard R Bristow Robert G RG Boutros Paul C PC Fraser Michael M Cooke Susanna S Raine Keiran K Jones David D Menzies Andrew A Stebbings Lucy L Hinton Jon J Teague Jon J McLaren Stuart S Mudie Laura L Hardy Claire C Anderson Elizabeth E Joseph Olivia O Goody Victoria V Robinson Ben B Maddison Mark M Gamble Stephen S Greenman Christopher C Berney Dan D Hazell Steven S Livni Naomi N Fisher Cyril C Ogden Christopher C Kumar Pardeep P Thompson Alan A Woodhouse Christopher C Nicol David D Mayer Erik E Dudderidge Tim T Shah Nimish C NC Gnanapragasam Vincent V Voet Thierry T Campbell Peter P Futreal Andrew A Easton Douglas D Warren Anne Y AY Foster Christopher S CS Stratton Michael R MR Whitaker Hayley C HC McDermott Ultan U Brewer Daniel S DS Neal David E DE

Nature genetics 20150302 4

Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational proces ...[more]

PMID: 25730763

Similar Datasets

Project description:BackgroundCommercial gene expression assays are guiding clinical decision making in patients with prostate cancer, particularly when considering active surveillance. Given heterogeneity and multifocality of primary prostate cancer, such assays should ideally be robust to the coexistence of unsampled higher grade disease elsewhere in the prostate in order to have clinical utility. Herein, we comprehensively evaluated transcriptomic profiles of primary multifocal prostate cancer to assess robustness to clinically relevant multifocality.MethodsWe designed a comprehensive, multiplexed targeted RNA-sequencing assay capable of assessing multiple transcriptional classes and deriving commercially available prognostic signatures, including the Myriad Prolaris Cell Cycle Progression score, the Oncotype DX Genomic Prostate Score, and the GenomeDX Decipher Genomic Classifier. We applied this assay to a retrospective, multi-institutional cohort of 156 prostate cancer samples. Derived commercial biomarker scores for 120 informative primary prostate cancer samples from 44 cases were determined and compared.ResultsDerived expression scores were positively correlated with tumor grade (rS = 0.53-0.73; all P < 0.001), both within the same case and across the entire cohort. In cases of extreme grade-discordant multifocality (co-occurrence of grade group 1 [GG1] and ?GG4 foci], gene expression scores were significantly lower in low- (GG1) versus high-grade (?GG4) foci (all P < 0.001). No significant differences in expression scores, however, were observed between GG1 foci from prostates with and without coexisting higher grade cancer (all P > 0.05).ConclusionsMultifocal, low-grade and high-grade prostate cancer foci exhibit distinct prognostic expression signatures. These findings demonstrate that prognostic RNA expression assays performed on low-grade prostate cancer biopsy tissue may not provide meaningful information on the presence of coexisting unsampled aggressive disease.FundingProstate Cancer Foundation, National Institutes of Health (U01 CA214170, R01 CA183857, University of Michigan Prostate Specialized Program of Research Excellence [S.P.O.R.E.] P50 CA186786-05, Weill Cornell Medicine S.P.O.R.E. P50 CA211024-01A1), Men of Michigan Prostate Cancer Research Fund, University of Michigan Comprehensive Cancer Center core grant (2-P30-CA-046592-24), A. Alfred Taubman Biomedical Research Institute, and Department of Defense.

Dataset Information

Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

Publications

Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets