Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.
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.
Division of Genetics and Epidemiology, The Institute Of Cancer Research, London, UK.|Department of Biological Sciences University of East Anglia, Norwich, UK.|Norwich Medical School, University of East Anglia, Norwich, UK.
Colin S
CS
Cooper
Division of Genetics and Epidemiology, The Institute Of Cancer Research, London, UK.|Royal Marsden NHS Foundation Trust, London and Sutton, UK.
Rosalind
R
Eeles
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
David C
DC
Wedge
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.|Human Genome Laboratory, Department of Human Genetics, VIB and KU Leuven, Leuven, Belgium.|Cancer Research UK London Research Institute, London, UK.
Peter
P
Van Loo
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Gunes
G
Gundem
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Ludmil B
LB
Alexandrov
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Barbara
B
Kremeyer
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Adam
A
Butler
Statistics and Computational Biology Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, UK.
Andrew G
AG
Lynch
Division of Genetics and Epidemiology, The Institute Of Cancer Research, London, UK.
Niedzica
N
Camacho
Urological Research Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, UK.
Charlie E
CE
Massie
Urological Research Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, UK.
Jonathan
J
Kay
Urological Research Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, UK.
Hayley J
HJ
Luxton
Division of Genetics and Epidemiology, The Institute Of Cancer Research, London, UK.
Sandra
S
Edwards
Division of Genetics and Epidemiology, The Institute Of Cancer Research, London, UK.
ZSofia
Z
Kote-Jarai
Royal Marsden NHS Foundation Trust, London and Sutton, UK.
Nening
N
Dennis
Division of Genetics and Epidemiology, The Institute Of Cancer Research, London, UK.
Sue
S
Merson
Division of Genetics and Epidemiology, The Institute Of Cancer Research, London, UK.
Daniel
D
Leongamornlert
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Jorge
J
Zamora
Department of Histopathology, St Georges Hospital, London, UK.
Cathy
C
Corbishley
Royal Marsden NHS Foundation Trust, London and Sutton, UK.
Sarah
S
Thomas
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Serena
S
Nik-Zainal
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Sarah
S
O'Meara
Division of Genetics and Epidemiology, The Institute Of Cancer Research, London, UK.
Lucy
L
Matthews
Norwich Medical School, University of East Anglia, Norwich, UK.
Jeremy
J
Clark
Norwich Medical School, University of East Anglia, Norwich, UK.
Rachel
R
Hurst
Institute of Food Research, Norwich Research Park, Norwich, UK.
Richard
R
Mithen
Department of Medical Biophysics, University of Toronto, Toronto, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, Canada.|Princess Margaret Cancer Centre-University Health Network, Toronto, Canada.
Robert G
RG
Bristow
Department of Medical Biophysics, University of Toronto, Toronto, Canada.|Informatics and Bio-Computing, Ontario Institute for Cancer Research, Toronto, Canada.|Department Pharmacology & Toxicology, University of Toronto, Toronto, Canada.
Paul C
PC
Boutros
Department of Radiation Oncology, University of Toronto, Toronto, Canada.|Princess Margaret Cancer Centre-University Health Network, Toronto, Canada.
Michael
M
Fraser
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Susanna
S
Cooke
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Keiran
K
Raine
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
David
D
Jones
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Andrew
A
Menzies
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Lucy
L
Stebbings
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Jon
J
Hinton
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Jon
J
Teague
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Stuart
S
McLaren
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Laura
L
Mudie
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Claire
C
Hardy
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Elizabeth
E
Anderson
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Olivia
O
Joseph
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Victoria
V
Goody
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Ben
B
Robinson
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Mark
M
Maddison
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Stephen
S
Gamble
School of Computing Sciences, University of East Anglia, Norwich, UK.
Christopher
C
Greenman
Department of Molecular Oncology, Barts Cancer Centre, Barts and the London School of Medicine and Dentistry, London, UK.
Dan
D
Berney
Royal Marsden NHS Foundation Trust, London and Sutton, UK.
Steven
S
Hazell
Royal Marsden NHS Foundation Trust, London and Sutton, UK.
Naomi
N
Livni
Royal Marsden NHS Foundation Trust, London and Sutton, UK.
Cyril
C
Fisher
Royal Marsden NHS Foundation Trust, London and Sutton, UK.
Christopher
C
Ogden
Royal Marsden NHS Foundation Trust, London and Sutton, UK.
Pardeep
P
Kumar
Royal Marsden NHS Foundation Trust, London and Sutton, UK.
Alan
A
Thompson
Royal Marsden NHS Foundation Trust, London and Sutton, UK.
Christopher
C
Woodhouse
Royal Marsden NHS Foundation Trust, London and Sutton, UK.
David
D
Nicol
Royal Marsden NHS Foundation Trust, London and Sutton, UK.
Erik
E
Mayer
Royal Marsden NHS Foundation Trust, London and Sutton, UK.
Tim
T
Dudderidge
Urological Research Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, UK.
Nimish C
NC
Shah
Urological Research Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, UK.
Vincent
V
Gnanapragasam
Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
Thierry
T
Voet
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Peter
P
Campbell
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Andrew
A
Futreal
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Douglas
D
Easton
Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Anne Y
AY
Warren
University of Liverpool, Liverpool, UK.|HCA Pathology Laboratories, London, UK.
Christopher S
CS
Foster
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Michael R
MR
Stratton
Urological Research Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, UK.
Hayley C
HC
Whitaker
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Ultan
U
McDermott
Division of Genetics and Epidemiology, The Institute Of Cancer Research, London, UK.|Norwich Medical School, University of East Anglia, Norwich, UK.|The Genome Analysis Centre, Norwich, UK.
Daniel S
DS
Brewer
Urological Research Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, UK.|Department of Surgical Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
David E
DE
Neal
D016022:Case-Control Studies; D019070:Cell Lineage / Q000235:genetics; D060965:Clonal Evolution / Q000235:genetics*; D002999:Clone Cells / Q000473:pathology; D004252:DNA Mutational Analysis; D006801:Humans; D008297:Male; D009154:Mutation; D009378:Neoplasms, Multiple Primary / Q000235:genetics*; D010802:Phylogeny; D011467:Prostate / Q000166:cytology* / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*