Evolutionary history of human colitis-associated colorectal cancer. Issue 6 (10th July 2018)

• Record Type: Journal Article
• Authors: Baker, Ann-Marie; Cross, William; Curtius, Kit; Al Bakir, Ibrahim; Choi, Chang-Ho Ryan; Davis, Hayley Louise; Temko, Daniel; Biswas, Sujata; Martinez, Pierre; Williams, Marc J; Lindsay, James O; Feakins, Roger; Vega, Roser; Hayes, Stephen J; Tomlinson, Ian P M; McDonald, Stuart A C; Moorghen, Morgan; Silver, Andrew; East, James E; Wright, Nicholas A; Wang, Lai Mun; Rodriguez-Justo, Manuel; Jansen, Marnix; Hart, Ailsa L; Leedham, Simon J; Graham, Trevor A
• Is Part Of: Gut. Volume 68:Issue 6(2019)
• Page Start: 985
• Page End: 995
• Publication Date: 2018-07-10
• Subjects: inflammatory bowel disease -- colorectal cancer -- dysplasia -- IBD - genetics; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2018-316191
• Languages: English
• ISSNs: 0017-5749

Abstract

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.