Carbon dating cancer: defining the chronology of metastatic progression in colorectal cancer.
Patients often ask oncologists how long a cancer has been present before causing symptoms or spreading to other organs. The evolutionary trajectory of cancers can be defined using phylogenetic approaches but lack of chronological references makes dating the exact onset of tumours very challenging.



Here, we describe the case of a colorectal cancer (CRC) patient presenting with synchronous lung metastasis and metachronous thyroid, chest wall and urinary tract metastases over the course of 5 years. The chest wall metastasis was caused by needle tract seeding, implying a known time of onset. Using whole genome sequencing data from primary and metastatic sites we inferred the complete chronology of the cancer by exploiting the time of needle tract seeding as an in vivo 'stopwatch'. This approach allowed us to follow the progression of the disease back in time, dating each ancestral node of the phylogenetic tree in the past history of the tumour. We used a Bayesian phylogenomic approach, which accounts for possible dynamic changes in mutational rate, to reconstruct the phylogenetic tree and effectively 'carbon date' the malignant progression.



The primary colon cancer emerged between 5 and 8 years before the clinical diagnosis. The primary tumour metastasized to the lung and the thyroid within a year from its onset. The thyroid lesion presented as a tumour-to-tumour deposit within a benign Hurthle adenoma. Despite rapid metastatic progression from the primary tumour, the patient showed an indolent disease course. Primary cancer and metastases were microsatellite stable and displayed low chromosomal instability. Neo-antigen analysis suggested minimal immunogenicity.



Our data provide the first in vivo experimental evidence documenting the timing of metastatic progression in CRC and suggest that genomic instability might be more important than the metastatic potential of the primary cancer in dictating CRC fate.
Division of Molecular Pathology, The Institute of Cancer Research, Sutton.|Gastrointestinal Cancers and Lymphoma Unit, The Royal Marsden NHS Trust, Sutton.
H
H
Lote
Centre for Evolution and Cancer, The Institute of Cancer Research, London.
I
I
Spiteri
Centre for Evolution and Cancer, The Institute of Cancer Research, London.
L
L
Ermini
Centre for Evolution and Cancer, The Institute of Cancer Research, London.
A
A
Vatsiou
Department of Oncology, Crosshouse Hospital, Crosshouse, Kilmarnock.
A
A
Roy
Beatson West of Scotland Cancer Centre, Glasgow.
A
A
McDonald
Department of Pathology, Southern General Hospital, Glasgow.
N
N
Maka
Department of Pathology, Crosshouse Hospital, Crosshouse, Kilmarnock, UK.
M
M
Balsitis
Department of Oncology, Crosshouse Hospital, Crosshouse, Kilmarnock.
N
N
Bose
Department of Pathology and Diagnostics, ARC-NET Research Centre University of Verona, Verona, Italy.
M
M
Simbolo
Department of Pathology and Diagnostics, ARC-NET Research Centre University of Verona, Verona, Italy.
A
A
Mafficini
Division of Molecular Pathology, The Institute of Cancer Research, Sutton.
A
A
Lampis
Division of Molecular Pathology, The Institute of Cancer Research, Sutton.
J C
JC
Hahne
Division of Molecular Pathology, The Institute of Cancer Research, Sutton.
F
F
Trevisani
Gastrointestinal Cancers and Lymphoma Unit, The Royal Marsden NHS Trust, Sutton.
Z
Z
Eltahir
Division of Molecular Pathology, The Institute of Cancer Research, Sutton.
G
G
Mentrasti
Beatson West of Scotland Cancer Centre, Glasgow.
C
C
Findlay
Beatson West of Scotland Cancer Centre, Glasgow.
E A J
EAJ
Kalkman
Centre for Evolution and Cancer, The Institute of Cancer Research, London.
M
M
Punta
Centre for Evolution and Cancer, The Institute of Cancer Research, London.
B
B
Werner
Centre for Evolution and Cancer, The Institute of Cancer Research, London.
S
S
Lise
Centre for Evolution and Cancer, The Institute of Cancer Research, London.|Center for Evolution and Cancer, University of California San Francisco, San Francisco.|Center for Social Dynamics and Complexity, Center for Evolution and Medicine, Arizona State University, Department of Psychology
A
A
Aktipis
Centre for Evolution and Cancer, The Institute of Cancer Research, London.|Center for Evolution and Cancer, University of California San Francisco, San Francisco.|Biodesign Institute, Arizona State University, Tempe, USA.
C
C
Maley
Centre for Evolution and Cancer, The Institute of Cancer Research, London.
M
M
Greaves
Gastrointestinal Cancers and Lymphoma Unit, The Royal Marsden NHS Trust, Sutton.|Division of Cancer Therapeutics, The Institute of Cancer Research, Sutton, UK.
C
C
Braconi
Beatson West of Scotland Cancer Centre, Glasgow.
J
J
White
Department of Pathology and Diagnostics, ARC-NET Research Centre University of Verona, Verona, Italy.|Department of Medicine, Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy.
M
M
Fassan
Department of Pathology and Diagnostics, ARC-NET Research Centre University of Verona, Verona, Italy.
A
A
Scarpa
Centre for Evolution and Cancer, The Institute of Cancer Research, London.
A
A
Sottoriva
Division of Molecular Pathology, The Institute of Cancer Research, Sutton.|Gastrointestinal Cancers and Lymphoma Unit, The Royal Marsden NHS Trust, Sutton.
N
N
Valeri
D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D018450:Disease Progression; D016678:Genome; D006801:Humans; D009362:Neoplasm Metastasis
cancer evolution; metastatic colorectal carcinoma; mutational analysis; phylogenetic tree; synchronous metastases; whole genome sequencing