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Evolutionary history of human colitis-associated colorectal cancer.
- Source :
-
Gut [Gut] 2019 Jun; Vol. 68 (6), pp. 985-995. Date of Electronic Publication: 2018 Jul 10. - Publication Year :
- 2019
-
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.<br />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.<br />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.<br />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.<br />Competing Interests: Competing interests: None declared.<br /> (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)
- Subjects :
- Cell Transformation, Neoplastic genetics
Colonoscopy methods
Disease Progression
Female
Gene Expression Regulation, Neoplastic
Humans
Male
Middle Aged
Phylogeny
Polymorphism, Single Nucleotide genetics
Risk Assessment
Severity of Illness Index
Cell Transformation, Neoplastic pathology
Colitis, Ulcerative genetics
Colitis, Ulcerative pathology
Colorectal Neoplasms genetics
Colorectal Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1468-3288
- Volume :
- 68
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Gut
- Publication Type :
- Academic Journal
- Accession number :
- 29991641
- Full Text :
- https://doi.org/10.1136/gutjnl-2018-316191