Cancer Evolution: Darwin and Beyond

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2021 Aug 30

PMID 34459009

Citations 102

Authors

Roberto Vendramin

Kevin Litchfield

Charles Swanton

Affiliations

Soon will be listed here.

Abstract

Clinical and laboratory studies over recent decades have established branched evolution as a feature of cancer. However, while grounded in somatic selection, several lines of evidence suggest a Darwinian model alone is insufficient to fully explain cancer evolution. First, the role of macroevolutionary events in tumour initiation and progression contradicts Darwin's central thesis of gradualism. Whole-genome doubling, chromosomal chromoplexy and chromothripsis represent examples of single catastrophic events which can drive tumour evolution. Second, neutral evolution can play a role in some tumours, indicating that selection is not always driving evolution. Third, increasing appreciation of the role of the ageing soma has led to recent generalised theories of age-dependent carcinogenesis. Here, we review these concepts and others, which collectively argue for a model of cancer evolution which extends beyond Darwin. We also highlight clinical opportunities which can be grasped through targeting cancer vulnerabilities arising from non-Darwinian patterns of evolution.

Citing Articles

A new insight into the impact of copy number variations on cell cycle deregulation of luminal-type breast cancer.

Mahdi Khamaneh A, Jafari-Gharabaghlou D, Ansarin K, Pazooki P, Akbarpour Z, Naghili B Oncol Rev. 2025; 19:1516409.

PMID: 40017494 PMC: 11861078. DOI: 10.3389/or.2025.1516409.

A binary trait model reveals the fitness effects of HIV-1 escape from T cell responses.

Gao Y, Barton J Proc Natl Acad Sci U S A. 2025; 122(8):e2405379122.

PMID: 39970000 PMC: 11873823. DOI: 10.1073/pnas.2405379122.

Karyotype evolution of myelodysplastic syndrome and acute myeloid leukemia with TP53 mutations.

Matsumoto Y, Kato D, Muramatsu A, Sugitani M, Kobayashi T, Iwai T Int J Hematol. 2025; .

PMID: 39969773 DOI: 10.1007/s12185-025-03938-w.

Cancer immune evasion, immunoediting and intratumour heterogeneity.

Roerden M, Spranger S Nat Rev Immunol. 2025; .

PMID: 39748116 DOI: 10.1038/s41577-024-01111-8.

Modern biology of extrachromosomal DNA: A decade-long voyage of discovery.

Yang Q, Xie Y, Qiao K, Lim J, Wu S Cell Res. 2025; 35(1):11-22.

PMID: 39748050 PMC: 11701097. DOI: 10.1038/s41422-024-01054-8.

References

Aceto N, Bardia A, Miyamoto D, Donaldson M, Wittner B, Spencer J . Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014; 158(5):1110-1122. PMC: 4149753. DOI: 10.1016/j.cell.2014.07.013. View

. On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life. Br Foreign Med Chir Rev. 2018; 25(50):367-404. PMC: 5184128. View

Ling S, Hu Z, Yang Z, Yang F, Li Y, Lin P . Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution. Proc Natl Acad Sci U S A. 2015; 112(47):E6496-505. PMC: 4664355. DOI: 10.1073/pnas.1519556112. View

Fan J, Lee H, Lee S, Ryu D, Lee S, Xue C . Linking transcriptional and genetic tumor heterogeneity through allele analysis of single-cell RNA-seq data. Genome Res. 2018; 28(8):1217-1227. PMC: 6071640. DOI: 10.1101/gr.228080.117. View

Campbell P, Yachida S, Mudie L, Stephens P, Pleasance E, Stebbings L . The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature. 2010; 467(7319):1109-13. PMC: 3137369. DOI: 10.1038/nature09460. View

Pepper J, Findlay C, Kassen R, Spencer S, Maley C . Cancer research meets evolutionary biology. Evol Appl. 2015; 2(1):62-70. PMC: 3352411. DOI: 10.1111/j.1752-4571.2008.00063.x. View

Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C . Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med. 2005; 352(25):2589-97. DOI: 10.1056/NEJMoa043623. View

Gerstung M, Jolly C, Leshchiner I, Dentro S, Gonzalez S, Rosebrock D . The evolutionary history of 2,658 cancers. Nature. 2020; 578(7793):122-128. PMC: 7054212. DOI: 10.1038/s41586-019-1907-7. View

Oobatake Y, Shimizu N . Double-strand breakage in the extrachromosomal double minutes triggers their aggregation in the nucleus, micronucleation, and morphological transformation. Genes Chromosomes Cancer. 2019; 59(3):133-143. DOI: 10.1002/gcc.22810. View

10.

Morgan G . Emile Zuckerkandl, Linus Pauling, and the molecular evolutionary clock, 1959-1965. J Hist Biol. 2001; 31(2):155-78. DOI: 10.1023/a:1004394418084. View

11.

Verhaak R, Bafna V, Mischel P . Extrachromosomal oncogene amplification in tumour pathogenesis and evolution. Nat Rev Cancer. 2019; 19(5):283-288. PMC: 7168519. DOI: 10.1038/s41568-019-0128-6. View

12.

Campbell L, Polyak K . Breast tumor heterogeneity: cancer stem cells or clonal evolution?. Cell Cycle. 2007; 6(19):2332-8. DOI: 10.4161/cc.6.19.4914. View

13.

Machnik M, Oleksiewicz U . Dynamic Signatures of the Epigenome: Friend or Foe?. Cells. 2020; 9(3). PMC: 7140607. DOI: 10.3390/cells9030653. View

14.

Sottoriva A, Kang H, Ma Z, Graham T, Salomon M, Zhao J . A Big Bang model of human colorectal tumor growth. Nat Genet. 2015; 47(3):209-16. PMC: 4575589. DOI: 10.1038/ng.3214. View

15.

Hoadley K, Siegel M, Kanchi K, Miller C, Ding L, Zhao W . Tumor Evolution in Two Patients with Basal-like Breast Cancer: A Retrospective Genomics Study of Multiple Metastases. PLoS Med. 2016; 13(12):e1002174. PMC: 5140046. DOI: 10.1371/journal.pmed.1002174. View

16.

Ramalingam N, Jeffrey S . Future of Liquid Biopsies With Growing Technological and Bioinformatics Studies: Opportunities and Challenges in Discovering Tumor Heterogeneity With Single-Cell Level Analysis. Cancer J. 2018; 24(2):104-108. PMC: 5880298. DOI: 10.1097/PPO.0000000000000308. View

17.

De Mattos-Arruda L, Sammut S, Ross E, Bashford-Rogers R, Greenstein E, Markus H . The Genomic and Immune Landscapes of Lethal Metastatic Breast Cancer. Cell Rep. 2019; 27(9):2690-2708.e10. PMC: 6546974. DOI: 10.1016/j.celrep.2019.04.098. View

18.

Venkatesan S, Angelova M, Puttick C, Zhai H, Caswell D, Lu W . Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution. Cancer Discov. 2021; 11(10):2456-2473. PMC: 8487921. DOI: 10.1158/2159-8290.CD-20-0725. View

19.

Gatenby R, Silva A, Gillies R, Frieden B . Adaptive therapy. Cancer Res. 2009; 69(11):4894-903. PMC: 3728826. DOI: 10.1158/0008-5472.CAN-08-3658. View

20.

Naxerova K, Reiter J, Brachtel E, Lennerz J, van de Wetering M, Rowan A . Origins of lymphatic and distant metastases in human colorectal cancer. Science. 2017; 357(6346):55-60. PMC: 5536201. DOI: 10.1126/science.aai8515. View