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Evolution and progression of Barrett’s oesophagus to oesophageal cancer

Nature Reviews Cancer volume 21, pages 731–741 (2021)Cite this article

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Abstract

Cancer cells are shaped through an evolutionary process of DNA mutation, cell selection and population expansion. Early steps in this process are driven by a set of mutated driver genes and structural alterations to the genome through copy number gains or losses. Oesophageal adenocarcinoma (EAC) and the pre-invasive tissue, Barrett’s oesophagus (BE), provide an ideal example in which to observe and study this evolution. BE displays early genomic instability, specifically in copy number changes that may later be observed in EAC. Furthermore, these early changes result in patterns of progression (that is, ‘born bad’, gradual or catastrophic) that may help to describe the evolution of EAC. As only a small proportion of patients with BE will go on to develop cancer, a better understanding of these patterns and the resulting genomic changes should improve early detection in EAC and may provide clues for the evolution of cancer more broadly.

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Fig. 1: Histopathological progression for BE.
Fig. 2: Histological and molecular BE progression.
Fig. 3: Interactive risk prediction.

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Acknowledgements

The laboratory of R.C.F. is funded by a Programme Grant from the Medical Research Council (MRC) (RG84369), and Cancer Research UK provided funding for the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS)/International Cancer Genome Consortium (ICGC) oesophageal cancer programme (RG66287).

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Authors and Affiliations

  1. Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK

    Sarah Killcoyne & Rebecca C. Fitzgerald

  2. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK

    Sarah Killcoyne

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  1. Sarah Killcoyne
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  2. Rebecca C. Fitzgerald
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Both authors contributed equally to this article.

Corresponding author

Correspondence to Rebecca C. Fitzgerald.

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Competing interests

R.C.F. is named on patents for Cytosponge and related assays that have been licensed by the Medical Research Council (MRC) to Covidien GI Solutions (now Medtronic). R.C.F is a co-founder and shareholder of Cyted Ltd, an Early Detection company. S.K. declares no competing interests.

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Nature Reviews Cancer thanks M. Stachler, T. Wang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Acute myeloid leukaemia multistage predictions: https://cancer.sanger.ac.uk/aml-multistage/

GitHub — gerstung-lab/BarrettsProgressionRisk: https://github.com/gerstung-lab/BarrettsProgressionRisk

Interactive and Contextual RISk Calculator (IC-RISC): https://ic-risc.fredhutch.org/

Glossary

Kataegis

Localized hypermutation often several hundred base pairs in length.

Mutational signature

A combination of mutations (specifically single base-pair substitutions) that generates a specific pattern, or signature, relating to specific mutational processes.

Minor-in groove

DNA facing in to the histone core (minor-in).

Chromothripsis

Hundreds of clustered breaks occurring in a single catastrophic event affecting a limited number of chromosomes.

Breakage–fusion–bridge processes

Mechanisms of genomic instability initiated by telomeric end fusions following double-stranded breaks, which can result in repetitive cycles of fusions and breaks.

Extrachromosomal DNA

(Often extrachromosomal circular DNA). DNA found separate to the chromosomes and often contributing to higher copy numbers and altered gene expression in cancer.

Chromoplexy

Chains of rearrangements that result from the repair of double-stranded breakages.

Cytosponge

A non-endoscopic device for sampling cells within the oesophagus consisting of a pill with a sponge on a string that can be swallowed by the patient.

AUC ROC

(Area under the receiver operating characteristic curve). A performance metric for classification at various thresholds by plotting the true positive rate against the false positive rate.

Elastic-net regression model

A regularized regression method that combines the penalties of LASSO and ridge methods.

Long-segment BE

Barrett’s oesophagus (BE) replaces normal squamous epithelium along measurable lengths of the oesophagus from <1 cm to ≥3 cm extending from the junction of the stomach and the oesophagus.

Hiatal hernia

The upper part of the stomach bulges through the opening of the diaphragm (hiatus) into the oesophagus.

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Killcoyne, S., Fitzgerald, R.C. Evolution and progression of Barrett’s oesophagus to oesophageal cancer. Nat Rev Cancer 21, 731–741 (2021). https://doi.org/10.1038/s41568-021-00400-x

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