Evolutionary history of human colitis-associated colorectal cancer

被引:120
|
作者
Baker, Ann-Marie [1 ]
Cross, William [1 ]
Curtius, Kit [1 ]
Al Bakir, Ibrahim [1 ,2 ]
Choi, Chang-Ho Ryan [1 ,2 ]
Davis, Hayley Louise [3 ]
Temko, Daniel [1 ,4 ,5 ]
Biswas, Sujata [3 ]
Martinez, Pierre [1 ]
Williams, Marc J. [1 ,5 ,6 ]
Lindsay, James O. [7 ]
Feakins, Roger [8 ]
Vega, Roser [9 ]
Hayes, Stephen J. [10 ]
Tomlinson, Ian P. M. [11 ]
McDonald, Stuart A. C. [1 ]
Moorghen, Morgan [2 ]
Silver, Andrew [7 ]
East, James E. [12 ]
Wright, Nicholas A. [1 ]
Wang, Lai Mun [13 ]
Rodriguez-Justo, Manuel [14 ]
Jansen, Marnix [14 ]
Hart, Ailsa L. [2 ]
Leedham, Simon J. [3 ,12 ]
Graham, Trevor A. [1 ]
机构
[1] Queen Mary Univ London, Barts Canc Inst, Barts & London Sch Med & Dent, London, England
[2] St Marks Hosp, Inflammatory Bowel Dis Unit, London, England
[3] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England
[4] UCL, Dept Comp Sci, London, England
[5] UCL, Ctr Math & Phys Life Sci & Expt Biol CoMPLEX, London, England
[6] UCL, Dept Cell & Dev Biol, London, England
[7] Queen Mary Univ London, Blizard Inst, Barts & London Sch Med & Dent, London, England
[8] Royal London Hosp, Dept Histopathol, London, England
[9] Univ Coll London Hosp, Dept Gastroenterol, London, England
[10] Univ Manchester, Salford Royal NHS Fdn Trust, Dept Histopathol, Manchester, Lancs, England
[11] Univ Birmingham, Inst Canc & Genom Sci, Canc Genet & Evolut Lab, Birmingham, W Midlands, England
[12] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Med, Translat Gastroenterol Unit, Oxford, England
[13] John Radcliffe Hosp, Cellular Pathol, Oxford, England
[14] Univ Coll London Hosp, Dept Histopathol, London, England
基金
英国医学研究理事会;
关键词
INFLAMMATORY-BOWEL-DISEASE; COLONOSCOPIC SURVEILLANCE PROGRAM; ULCERATIVE-COLITIS; FIELD CANCERIZATION; CROHNS-DISEASE; DNA ANEUPLOIDY; MUTATIONS; P53; DYSPLASIA; COLON;
D O I
10.1136/gutjnl-2018-316191
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Objective I BD 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 E xome 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 ageingassociated mutational processes. Non-dysplastic mucosa had considerable mutation burden (median 47 SNAs), including mutations shared with the neighbouring CACRC, 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 E volutionary 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.
引用
收藏
页码:985 / 995
页数:11
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