Journal
NATURE GENETICS
Volume 47, Issue 4, Pages 367-U118Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3221
Keywords
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Categories
Funding
- Cancer Research UK [C5047/A14835]
- Dallaglio Foundation
- Wellcome Trust
- Bob Champion Cancer Trust
- Orchid Cancer Appeal
- RoseTrees Trust
- North West Cancer Research Fund
- Big C
- King family
- Grand Charity of Freemasons
- Research Foundation Flanders (FWO)
- Biomedical Research Centre at the Institute of Cancer Research - National Institute for Health Research
- Royal Marsden NHS Foundation Trust - National Institute for Health Research
- National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT) [G0500966/75466]
- Biotechnology and Biological Sciences Research Council [BBS/E/T/000PR5885, BBS/E/T/000PR6193, BBS/E/F/00042686, BBS/E/F/00044431] Funding Source: researchfish
- Cancer Research UK [17528, 14835, 15007] Funding Source: researchfish
- The Francis Crick Institute [10202] Funding Source: researchfish
- Versus Arthritis
- Cancer Research UK [20406] Funding Source: researchfish
- BBSRC [BBS/E/F/00042686, BBS/E/T/000PR6193, BBS/E/F/00044431, BBS/E/T/000PR5885] Funding Source: UKRI
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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.
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