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Nat Ecol Evol. 2018 Oct;2(10):1661-1672. doi: 10.1038/s41559-018-0642-z. Epub 2018 Aug 31.

The evolutionary landscape of colorectal tumorigenesis.

Author information

1
Evolution and Cancer Laboratory, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
2
Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
3
Bone Tumour Reference Center at the Institute of Pathology, University Hospital Basel, Basel, Switzerland.
4
Organismal and Evolutionary Biology Research Programme, Department of Computer Science, Institute of Biotechnology, Helsinki Institute for Information Technology HIIT, University of Helsinki, Helsinki, Finland.
5
CoMPLEX, Department of Computer Science, University College London, London, UK.
6
Gastrointestinal Stem Cell Biology Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
7
Cancer Bioinfomatics Group, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
8
Gastrointestinal Cancer Genetics Laboratory, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
9
Integrated Mathematical Oncology Department, Moffitt Comprehensive Cancer Centre, Tampa, FL, USA.
10
Institute of Pathology, University of Bern, Bern, Switzerland.
11
Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
12
Big Data Institute, University of Oxford, Oxford, UK.
13
Institute of Mathematics and Physics, Faculty of Mechanical Engineering, Slovak University of Technology in Bratislava, Bratislava, Slovakia.
14
Department of Oncology, University of Oxford, Oxford, UK.
15
Department of Research Pathology, Cancer Institute, University College London, London, UK.
16
Department of Surgery, University Hospitals Birmingham, Birmingham, UK.
17
Department of Colorectal Surgery, Cancer Centre, Churchill Hospital, Oxford University Hospital NHS Foundation Trust, Oxford, UK.
18
Translational Gastroenterology Unit, University of Oxford, John Radcliffe Hospital, Oxford, UK.
19
Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
20
Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
21
Department of Biomedicine, University of Basel, Basel, Switzerland.
22
Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.
23
Evolution and Cancer Laboratory, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. t.graham@qmul.ac.uk.
24
Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. i.tomlinson@bham.ac.uk.
25
Department of Histopathology, University Hospitals Birmingham, Birmingham, UK. i.tomlinson@bham.ac.uk.

Abstract

The evolutionary events that cause colorectal adenomas (benign) to progress to carcinomas (malignant) remain largely undetermined. Using multi-region genome and exome sequencing of 24 benign and malignant colorectal tumours, we investigate the evolutionary fitness landscape occupied by these neoplasms. Unlike carcinomas, advanced adenomas frequently harbour sub-clonal driver mutations-considered to be functionally important in the carcinogenic process-that have not swept to fixation, and have relatively high genetic heterogeneity. Carcinomas are distinguished from adenomas by widespread aneusomies that are usually clonal and often accrue in a 'punctuated' fashion. We conclude that adenomas evolve across an undulating fitness landscape, whereas carcinomas occupy a sharper fitness peak, probably owing to stabilizing selection.

PMID:
30177804
PMCID:
PMC6152905
DOI:
10.1038/s41559-018-0642-z
[Indexed for MEDLINE]
Free PMC Article

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