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.
| Original language | English |
|---|---|
| Pages (from-to) | 1661-1672 |
| Number of pages | 12 |
| Journal | Nature Ecology and Evolution |
| Volume | 2 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 31 Aug 2018 |
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ASJC Scopus subject areas
- Ecology, Evolution, Behavior and Systematics
- Ecology
Cite this
The evolutionary landscape of colorectal tumorigenesis. / Cross, William; Kovac, Michal; Mustonen, Ville; Temko, Daniel; Davis, Hayley; Biswas, Sujata; Baker, Ann Marie; Arnold, Roland; Chegwidden, Laura; Gatenbee, Chandler; Anderson, Alexander R.; Koelzer, Viktor H.; Martinez, Pierre; Jiang, Xiaowei; Domingo, Enric; Woodcock, Dan J.; Feng, Yun; Kovacova, Monika; Maughan, Tim; The S:CORT Consortium; Adams, Richard; Bach, Simon; Beggs, Andrew; Brown, Louise; Buffa, Francesca; Cazier, Jean Baptiste; Domingo, Enric; Blake, Andrew; Wu, Che Hsi; Chatzpili, Ekaterina; Richman, Susan; Dunne, Philip; Harkin, Paul; Higgins, Geoff; Hill, Jim; Holmes, Chris; Horgan, Denis; Kaplan, Rick; Kennedy, Richard; Lawler, Mark; Leedham, Simon; Maughan, Tim; McDermott, Ultan; McKenna, Gillies; Middleton, Gary; Morton, Dion; Murray, Graeme; Quirke, Phil; Salto-Tellez, Manuel; Samuel, Les; Schuh, Anna; Jansen, Marnix ; Rodriguez-Justo, Manuel ; Ashraf, Shazad; Guy, Richard ; Cunningham, Christopher ; East, James E. ; Wedge, David C. ; Wang, Lai Mun ; Palles, Claire; Heinimann, Karl ; Sottoriva, Andrea; Leedham, Simon J. ; Graham, Trevor A. (Corresponding Author); Tomlinson, Ian P. M. (Corresponding Author).
In: Nature Ecology and Evolution, Vol. 2, No. 10, 31.08.2018, p. 1661-1672.Research output: Contribution to journal › Article
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TY - JOUR
T1 - The evolutionary landscape of colorectal tumorigenesis
AU - Cross, William
AU - Kovac, Michal
AU - Mustonen, Ville
AU - Temko, Daniel
AU - Davis, Hayley
AU - Biswas, Sujata
AU - Baker, Ann Marie
AU - Arnold, Roland
AU - Chegwidden, Laura
AU - Gatenbee, Chandler
AU - Anderson, Alexander R.
AU - Koelzer, Viktor H.
AU - Martinez, Pierre
AU - Jiang, Xiaowei
AU - Domingo, Enric
AU - Woodcock, Dan J.
AU - Feng, Yun
AU - Kovacova, Monika
AU - Maughan, Tim
AU - The S:CORT Consortium
AU - Adams, Richard
AU - Bach, Simon
AU - Beggs, Andrew
AU - Brown, Louise
AU - Buffa, Francesca
AU - Cazier, Jean Baptiste
AU - Domingo, Enric
AU - Blake, Andrew
AU - Wu, Che Hsi
AU - Chatzpili, Ekaterina
AU - Richman, Susan
AU - Dunne, Philip
AU - Harkin, Paul
AU - Higgins, Geoff
AU - Hill, Jim
AU - Holmes, Chris
AU - Horgan, Denis
AU - Kaplan, Rick
AU - Kennedy, Richard
AU - Lawler, Mark
AU - Leedham, Simon
AU - Maughan, Tim
AU - McDermott, Ultan
AU - McKenna, Gillies
AU - Middleton, Gary
AU - Morton, Dion
AU - Murray, Graeme
AU - Quirke, Phil
AU - Salto-Tellez, Manuel
AU - Samuel, Les
AU - Schuh, Anna
AU - Jansen, Marnix
AU - Rodriguez-Justo, Manuel
AU - Ashraf, Shazad
AU - Guy, Richard
AU - Cunningham, Christopher
AU - East, James E.
AU - Wedge, David C.
AU - Wang, Lai Mun
AU - Palles, Claire
AU - Heinimann, Karl
AU - Sottoriva, Andrea
AU - Leedham, Simon J.
AU - Graham, Trevor A.
AU - Tomlinson, Ian P. M.
N1 - Supplementary information is available for this paper at https://doi.org/10.1038/ s41559-018-0642-z Raw data are available via the European Genome-Phenome Archive (https://ega-archive.org/) accession code: EGAS00001003066. S.J.L., T.A.G. (A19771) and I.P.M.T. (A27327) are funded by Cancer Research UK. We acknowledge core funding provided to the Wellcome Trust Centre for Human Genetics from the Wellcome Trust (090532/Z/09/Z). T.A.G. and S.J.L. were also supported by the Bowel and Cancer Research small grant scheme. T.A.G. was also supported by the Wellcome Trust (202778/Z/16/Z). V.M. was supported in part by funding from the Wellcome Trust (098051). M. Kovac was supported by the Krebsligabeider Basel (grant no. KLBB-12-2013) and the University of Basel (‘Förderung exzellenter Nachwuchsforschender’). A-M.B. also acknowledges funding from Cancer Research UK (A14895). D.C.W. is supported by the Li Ka Shing Foundation. X.J. and I.P.M.T. are supported by an ERC advanced grant (EVOCAN-340560). The S:CORT study is funded by the MRC and Cancer Research UK. K.H is supported by Krebsliga Zentralschweiz. A.S. is supported by the Wellcome Trust (202778/B/16/Z), Cancer Research UK (A22909) and the Chris Rokos Fellowship in Evolution and Cancer. This work was also supported a Wellcome Trust award to the Centre for Evolution and Cancer (105104/Z/14/Z). J.E.E. was funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). V.H.K. was funded by the Swiss National Science Foundation (P2SKP3_168322 / 1 and P2SKP3_168322 / 2). D.T. acknowledges funding from the EPSRC (grant no.: EP/F500351/1).
PY - 2018/8/31
Y1 - 2018/8/31
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85053310111&partnerID=8YFLogxK
U2 - 10.1038/s41559-018-0642-z
DO - 10.1038/s41559-018-0642-z
M3 - Article
AN - SCOPUS:85053310111
VL - 2
SP - 1661
EP - 1672
JO - Nature Ecology & Evolution
JF - Nature Ecology & Evolution
SN - 2397-334X
IS - 10
ER -