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Evolutionary dynamics in Barrett oesophagus: implications for surveillance, risk stratification and therapy

Abstract

Cancer development is a dynamic evolutionary process characterized by marked intratumoural heterogeneity at the genetic, epigenetic and phenotypic levels. Barrett oesophagus, the pre-malignant condition to oesophageal adenocarcinoma (EAC), is an exemplary system to longitudinally study the evolution of malignancy. Evidence has emerged of Barrett oesophagus lesions pre-programmed for progression to EAC many years before clinical detection, indicating a considerable window for therapeutic intervention. In this Review, we explore the mechanisms underlying clonal expansion and contraction that establish the Barrett oesophagus clonal mosaicism over time and space and discuss intrinsic genotypic and extrinsic environmental drivers that direct the evolutionary trajectory of Barrett oesophagus towards a malignant phenotype. We propose that understanding and exploiting the evolutionary dynamics of Barrett oesophagus will identify novel therapeutic targets, improve prognostic tools and offer the opportunity for personalized surveillance programmes geared to prevent progression to EAC.

Key points

  • Longitudinal surveillance of Barrett oesophagus offers an exemplary opportunity to study lesion evolution over time and space and during the progression to oesophageal adenocarcinoma.

  • Distinct evolutionary patterns exist between non-progressing and progressing Barrett oesophagus with evidence for protracted evolutionary dynamics occurring over many years.

  • Chronic inflammation due to reflux accelerates evolution through mutagenesis and provides a selective pressure for mutant clones that are viable in the harsh environment and can rapidly repopulate the ulcerated mucosa.

  • The measurement of evolutionary dynamics in Barrett oesophagus lesions is a potentially powerful prognostic tool and identifies a wide window for therapeutic intervention and prevention of cancer in patients with Barrett oesophagus.

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Fig. 1: Evolutionary models in Barrett oesophagus.
Fig. 2: The role of inflammation in Barrett oesophagus.

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Acknowledgements

The authors acknowledge funding from: German Cancer Aid Society (Deutsche Krebshilfe) (M.S.), Cancer Research UK (R.J.H.), Cancer Research UK (A19771) (A.B. and T.A.G.), the US NIH via the Cancer Systems Biology Consortium U54 scheme (CA217376) (T.A.G.), German Research Foundation (DFG 3772/1) (M.Q.), Cancer Research UK PFA award (A21446) (S.A.C.M.) and a Cancer Research UK Grand Challenge award (STORMing Cancer, A29071) (S.A.C.M.).

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M.S. and R.J.H. wrote the first draft of the review. A.B., S.A.C.M., M.Q. and T.A.G. edited the review. All authors approved the final draft of the manuscript.

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Correspondence to Trevor A. Graham.

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Nature Reviews Gastroenterology & Hepatology thanks Rebecca Fitzgerald and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Dysplasia

Neoplastic epithelium that remains confined within the basement membrane of the epithelium.

Fitness

The average contribution of a genotype to the next generation. The fitness of a genotype is manifested through its phenotype, which is also affected by the environment. Fitness generally promotes both survival and reproduction.

Clonal expansion

Spatial expansion of a clone through increased proliferation due to an advantageous phenotype.

Genetic diversity

The multitude of genetic variation on which selection can act.

Intratumoural heterogeneity

Diversity within individual tumours at the genetic, epigenetic and transcriptomic level.

Clone

A group of cells that share a common genotype as they descend from a common ancestor.

Loss of heterozygosity

(LOH). Allelic imbalance by which a heterozygous somatic cell becomes homozygous because one of the two alleles gets lost.

Fixation

When a genetic alteration reaches 100% frequency in a cell population.

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Schmidt, M., Hackett, R.J., Baker, AM. et al. Evolutionary dynamics in Barrett oesophagus: implications for surveillance, risk stratification and therapy. Nat Rev Gastroenterol Hepatol 19, 95–111 (2022). https://doi.org/10.1038/s41575-021-00531-4

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