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Inflammatory bowel disease
Original article
Evolutionary history of human colitis-associated colorectal cancer
  1. Ann-Marie Baker1,
  2. William Cross1,
  3. Kit Curtius1,
  4. Ibrahim Al Bakir1,2,
  5. Chang-Ho Ryan Choi1,2,
  6. Hayley Louise Davis3,
  7. Daniel Temko1,4,5,
  8. Sujata Biswas3,
  9. Pierre Martinez1,
  10. Marc J Williams1,5,6,
  11. James O Lindsay7,
  12. Roger Feakins8,
  13. Roser Vega9,
  14. Stephen J Hayes10,
  15. Ian P M Tomlinson11,
  16. Stuart A C McDonald1,
  17. Morgan Moorghen2,
  18. Andrew Silver7,
  19. James E East12,
  20. Nicholas A Wright1,
  21. Lai Mun Wang13,
  22. Manuel Rodriguez-Justo14,
  23. Marnix Jansen14,
  24. Ailsa L Hart2,
  25. Simon J Leedham3,12,
  26. Trevor A Graham1
  1. 1 Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  2. 2 Inflammatory Bowel Disease Unit, St Mark’s Hospital, London, UK
  3. 3 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  4. 4 Department of Computer Science, University College London, London, UK
  5. 5 Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London, London, UK
  6. 6 Department of Cell and Developmental Biology, University College London, London, UK
  7. 7 Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  8. 8 Department of Histopathology, The Royal London Hospital, London, UK
  9. 9 Department of Gastroenterology, University College London Hospital, London, UK
  10. 10 Department of Histopathology, Salford Royal NHS Foundation Trust, University of Manchester, Manchester, UK
  11. 11 Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
  12. 12 Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
  13. 13 Cellular Pathology, John Radcliffe Hospital, Oxford, UK
  14. 14 Department of Histopathology, University College London Hospital, London, UK
  1. Correspondence to Dr Ann-Marie Baker and Dr Trevor A Graham, Barts Cancer Institute, Queen Mary University of London, London, UK; a.m.c.baker{at}qmul.ac.uk, t.graham{at}qmul.ac.uk and Professor Simon J Leedham, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; simonl{at}well.ox.ac.uk

Abstract

Objective IBD confers an increased lifetime risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) is molecularly distinct from sporadic CRC (S-CRC). Here we have dissected the evolutionary history of CA-CRC using multiregion sequencing.

Design Exome sequencing was performed on fresh-frozen multiple regions of carcinoma, adjacent non-cancerous mucosa and blood from 12 patients with CA-CRC (n=55 exomes), and key variants were validated with orthogonal methods. Genome-wide copy number profiling was performed using single nucleotide polymorphism arrays and low-pass whole genome sequencing on archival non-dysplastic mucosa (n=9), low-grade dysplasia (LGD; n=30), high-grade dysplasia (HGD; n=13), mixed LGD/HGD (n=7) and CA-CRC (n=19). Phylogenetic trees were reconstructed, and evolutionary analysis used to reveal the temporal sequence of events leading to CA-CRC.

Results 10/12 tumours were microsatellite stable with a median mutation burden of 3.0 single nucleotide alterations (SNA) per Mb, ~20% higher than S-CRC (2.5 SNAs/Mb), and consistent with elevated ageing-associated mutational processes. Non-dysplastic mucosa had considerable mutation burden (median 47 SNAs), including mutations shared with the neighbouring CA-CRC, indicating a precancer mutational field. CA-CRCs were often near triploid (40%) or near tetraploid (20%) and phylogenetic analysis revealed that copy number alterations (CNAs) began to accrue in non-dysplastic bowel, but the LGD/HGD transition often involved a punctuated ‘catastrophic’ CNA increase.

Conclusions Evolutionary genomic analysis revealed precancer clones bearing extensive SNAs and CNAs, with progression to cancer involving a dramatic accrual of CNAs at HGD. Detection of the cancerised field is an encouraging prospect for surveillance, but punctuated evolution may limit the window for early detection.

  • inflammatory bowel disease
  • colorectal cancer
  • dysplasia
  • IBD - genetics

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/gutjnl-2018-316191

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    Footnotes

    • A-MB, WC, KC, IAB and C-HRC are Joint first authors.

    • 31 ALH, SJL and TAG are Joint senior authors.

    • Contributors AMB performed experimental work, with HLD, IAB and CHRC assisting with DNA extractions. MM, MRJ, MJ, LMW and NAW performed histological analysis. CHRC, JOL, RF, RV, SACM, IAB, MM, SJH, SB, AS, JEE and LMW performed sample identification and collection. AMB, WC, KC, IAB, CHRC, DT, PM, IPMT, MW, SJL and TAG analysed the data. Figures were compiled by AMB, WC, KC, DT and MJ. ALH, SJL and TAG supervised the project. SJL and TAG designed the study and secured funding. AMB, SJL and TAG wrote the first draft of the manuscript and all authors read and approved the final version.

    • Funding This work was supported by Cancer Research UK (A14895, AMB and NAW; A19771, TAG; A16581, SJL), Crohn’s and Colitis UK (Research grant M/15/5 to SJL and TAG), Barts Charity (472-2300, TAG and KC), the Medical Research Council (MR/P00122X/1 to IAB, ALH and TAG), the St Mark’s Hospital Foundation Research Grant (RES198 to IAB, ALH, TAG), the Derek Willoughby Fund for Inflammatory Research (CHRC, ALH and TAG), UKRI Innovation/Rutherford Fund (KC), the Engineering and Physical Science Research Council (EP/F500351/1, DT), the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme (JEE and SJL), and the NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London (MRJ).

    • Disclaimer The role of the MCRC Biobank is to distribute samples and therefore cannot endorse studies performed or the interpretation of results.

    • Competing interests None declared.

    • Patient consent Not required.

    • Ethics approval London Stanmore committee, 11/LO/1613.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement All raw sequence data and array files are available on the EGA-GPA via accession number EGAS00001003028. Processed data (eg, mutation calls) are provided as supplementary material in this manuscript. Bioinformatics scripts to repeat our analysis are available at: https://github.com/BCI-EvoCa/Evo_history_CACRC.