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Nat Genet. 2015 Apr;47(4):367-372. doi: 10.1038/ng.3221. Epub 2015 Mar 2.

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

Author information

1
Division of Genetics and Epidemiology, The Institute Of Cancer Research, London, UK.
2
Department of Biological Sciences University of East Anglia, Norwich, UK.
3
Norwich Medical School, University of East Anglia, Norwich, UK.
4
Royal Marsden NHS Foundation Trust, London and Sutton, UK.
5
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
6
Human Genome Laboratory, Department of Human Genetics, VIB and KU Leuven, Leuven, Belgium.
7
Cancer Research UK London Research Institute, London, UK.
8
Statistics and Computational Biology Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, UK.
9
Urological Research Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, UK.
10
Department of Histopathology, St Georges Hospital, London, UK.
11
Institute of Food Research, Norwich Research Park, Norwich, UK.
12
Department of Medical Biophysics, University of Toronto, Toronto, Canada.
13
Department of Radiation Oncology, University of Toronto, Toronto, Canada.
14
Princess Margaret Cancer Centre-University Health Network, Toronto, Canada.
15
Informatics and Bio-Computing, Ontario Institute for Cancer Research, Toronto, Canada.
16
Department Pharmacology & Toxicology, University of Toronto, Toronto, Canada.
17
School of Computing Sciences, University of East Anglia, Norwich, UK.
18
Department of Molecular Oncology, Barts Cancer Centre, Barts and the London School of Medicine and Dentistry, London, UK.
19
Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
20
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
21
Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
22
University of Liverpool, Liverpool, UK.
23
HCA Pathology Laboratories, London, UK.
24
The Genome Analysis Centre, Norwich, UK.
25
Department of Surgical Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
#
Contributed equally

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.

PMID:
25730763
PMCID:
PMC4380509
DOI:
10.1038/ng.3221
[Indexed for MEDLINE]
Free PMC Article

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