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Gut. 2019 Jun;68(6):985-995. doi: 10.1136/gutjnl-2018-316191. Epub 2018 Jul 10.

Evolutionary history of human colitis-associated colorectal cancer.

Author information

1
Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
2
Inflammatory Bowel Disease Unit, St Mark's Hospital, London, UK.
3
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
4
Department of Computer Science, University College London, London, UK.
5
Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London, London, UK.
6
Department of Cell and Developmental Biology, University College London, London, UK.
7
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
8
Department of Histopathology, The Royal London Hospital, London, UK.
9
Department of Gastroenterology, University College London Hospital, London, UK.
10
Department of Histopathology, Salford Royal NHS Foundation Trust, University of Manchester, Manchester, UK.
11
Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
12
Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
13
Cellular Pathology, John Radcliffe Hospital, Oxford, UK.
14
Department of Histopathology, University College London Hospital, London, 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.

KEYWORDS:

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

PMID:
29991641
PMCID:
PMC6580738
DOI:
10.1136/gutjnl-2018-316191
[Indexed for MEDLINE]
Free PMC Article

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