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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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Cooper, CS 
Eeles, R 
Wedge, DC 
Van Loo, P 
Gundem, G 

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.

Description

Keywords

DNA sequencing, prostate cancer

Journal Title

Nature Genetics

Conference Name

Journal ISSN

1061-4036
1546-1718

Volume Title

47

Publisher

Springer Nature
Sponsorship
Cancer Research UK (via Institute of Cancer Research (ICR)) (C5047/A22530)
This work was funded by Cancer Research UK (grant C5047/A14835), the Dallaglio Foundation and the Wellcome Trust. We also acknowledge support from the Bob Champion Cancer Trust, the Orchid Cancer Appeal, the RoseTrees Trust, the North West Cancer Research Fund, Big C, the King family, the Grand Charity of Freemasons, and the Research Foundation Flanders (FWO). We thank D. Holland from the Infrastructure Management Team and P. Clapham from the Informatics Systems Group at the Wellcome Trust Sanger Institute. We acknowledge the Biomedical Research Centre at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, supported by the National Institute for Health Research. We acknowledge support from the National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT) collaborative (grant G0500966/75466). We thank the National Institute for Health Research, Hutchison Whampoa Limited and the Human Research Tissue Bank (Addenbrooke's Hospital), the Cancer Research UK Cambridge Research Institute Histopathology, the In-situ Hybridisation Core Facility, the Genomics Core Facility Cambridge and the Cambridge University Hospitals Media Studio.