RT Journal Article
SR Electronic
T1 Evolutionary history of human colitis-associated colorectal cancer
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 985
OP 995
DO 10.1136/gutjnl-2018-316191
VO 68
IS 6
A1 Ann-Marie Baker
A1 William Cross
A1 Kit Curtius
A1 Ibrahim Al Bakir
A1 Chang-Ho Ryan Choi
A1 Hayley Louise Davis
A1 Daniel Temko
A1 Sujata Biswas
A1 Pierre Martinez
A1 Marc J Williams
A1 James O Lindsay
A1 Roger Feakins
A1 Roser Vega
A1 Stephen J Hayes
A1 Ian P M Tomlinson
A1 Stuart A C McDonald
A1 Morgan Moorghen
A1 Andrew Silver
A1 James E East
A1 Nicholas A Wright
A1 Lai Mun Wang
A1 Manuel Rodriguez-Justo
A1 Marnix Jansen
A1 Ailsa L Hart
A1 Simon J Leedham
A1 Trevor A Graham
YR 2019
UL http://gut.bmj.com/content/68/6/985.abstract
AB 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.