TY - JOUR T1 - Evolutionary history of human colitis-associated colorectal cancer JF - Gut JO - Gut SP - 985 LP - 995 DO - 10.1136/gutjnl-2018-316191 VL - 68 IS - 6 AU - Ann-Marie Baker AU - William Cross AU - Kit Curtius AU - Ibrahim Al Bakir AU - Chang-Ho Ryan Choi AU - Hayley Louise Davis AU - Daniel Temko AU - Sujata Biswas AU - Pierre Martinez AU - Marc J Williams AU - James O Lindsay AU - Roger Feakins AU - Roser Vega AU - Stephen J Hayes AU - Ian P M Tomlinson AU - Stuart A C McDonald AU - Morgan Moorghen AU - Andrew Silver AU - James E East AU - Nicholas A Wright AU - Lai Mun Wang AU - Manuel Rodriguez-Justo AU - Marnix Jansen AU - Ailsa L Hart AU - Simon J Leedham AU - Trevor A Graham Y1 - 2019/06/01 UR - http://gut.bmj.com/content/68/6/985.abstract N2 - 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. ER -