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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

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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

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Project description:BackgroundUp to 80% of cases of prostate cancer present with multifocal independent tumour lesions leading to the concept of a field effect present in the normal prostate predisposing to cancer development. In the present study we applied Whole Genome DNA Sequencing (WGS) to a group of morphologically normal tissue (n = 51), including benign prostatic hyperplasia (BPH) and non-BPH samples, from men with and men without prostate cancer. We assess whether the observed genetic changes in morphologically normal tissue are linked to the development of cancer in the prostate.ResultsSingle nucleotide variants (P = 7.0 × 10-03, Wilcoxon rank sum test) and small insertions and deletions (indels, P = 8.7 × 10-06) were significantly higher in morphologically normal samples, including BPH, from men with prostate cancer compared to those without. The presence of subclonal expansions under selective pressure, supported by a high level of mutations, were significantly associated with samples from men with prostate cancer (P = 0.035, Fisher exact test). The clonal cell fraction of normal clones was always higher than the proportion of the prostate estimated as epithelial (P = 5.94 × 10-05, paired Wilcoxon signed rank test) which, along with analysis of primary fibroblasts prepared from BPH specimens, suggests a stromal origin. Constructed phylogenies revealed lineages associated with benign tissue that were completely distinct from adjacent tumour clones, but a common lineage between BPH and non-BPH morphologically normal tissues was often observed. Compared to tumours, normal samples have significantly less single nucleotide variants (P = 3.72 × 10-09, paired Wilcoxon signed rank test), have very few rearrangements and a complete lack of copy number alterations.ConclusionsCells within regions of morphologically normal tissue (both BPH and non-BPH) can expand under selective pressure by mechanisms that are distinct from those occurring in adjacent cancer, but that are allied to the presence of cancer. Expansions, which are probably stromal in origin, are characterised by lack of recurrent driver mutations, by almost complete absence of structural variants/copy number alterations, and mutational processes similar to malignant tissue. Our findings have implications for treatment (focal therapy) and early detection approaches.

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

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