Low-coverage whole genome sequencing of low-grade dysplasia strongly predicts advanced neoplasia risk in ulcerative colitis

被引：2

作者：

Al Bakir, Ibrahim ^{[1
,2
,3
]}

Curtius, Kit ^{[1
,4
,5
,6
]}

Cresswell, George D. ^{[7
,8
]}

Grant, Heather E. ^{[7
]}

Nasreddin, Nadia ^{[9
]}

Smith, Kane ^{[1
,7
]}

Nowinski, Salpie ^{[1
,7
]}

Guo, Qingli ^{[1
,7
]}

Belnoue-Davis, Hayley L. ^{[9
]}

Fisher, Jennifer ^{[2
,7
]}

Clarke, Theo ^{[1
]}

Kimberley, Christopher ^{[1
]}

Mossner, Maximilian ^{[1
,7
]}

Dunne, Philip D. ^{[10
]}

Loughrey, Maurice B. ^{[11
,12
,13
]}

Speight, Ally ^{[14
]}

East, James E. ^{[15
]}

Wright, Nicholas A. ^{[1
]}

Rodriguez-Justo, Manuel ^{[16
,17
]}

Jansen, Marnix ^{[16
,17
]}

Moorghen, Morgan ^{[18
]}

Baker, Ann-Marie ^{[1
,7
]}

Leedham, Simon J. ^{[9
,15
]}

Hart, Ailsa L. ^{[2
,19
]}

Graham, Trevor A. ^{[1
,7
]}

机构：

[1] Queen Mary Univ London, Barts Canc Inst, London, England

[2] St Marks Hosp, Inflammatory Bowel Dis Unit, Harrow, England

[3] Chelsea & Westminster Hosp, London, England

[4] Univ Calif San Diego, Dept Med, Div Biomed Informat, La Jolla, CA 92093 USA

[5] VA San Diego Healthcare Syst, San Diego, CA 92161 USA

[6] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA

[7] Inst Canc Res, Ctr Evolut & Canc, London, England

[8] St Anna Childrens Canc Res Inst, Vienna, Austria

[9] Univ Oxford, Wellcome Ctr Human Genet, Oxford, England

[10] Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast, North Ireland

[11] Belfast Hlth & Social Care Trust, Cellular Pathol, Belfast, North Ireland

[12] Queens Univ Belfast, Ctr Publ Hlth, Belfast, North Ireland

[13] Queens Univ Belfast, Patrick G Johnston Canc Res, Belfast, North Ireland

[14] Newcastle upon Tyne Hosp NHS Trust, Dept Gastroenterol, Newcastle upon Tyne, England

[15] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Med, Translat Gastroenterol Unit, Oxford, England

[16] Univ Coll London Hosp, Dept Pathol, London, England

[17] UCL, UCL Canc Inst, London, England

[18] St Marks Hosp, Dept Histopathol, Harrow, England

[19] Imperial Coll London, Dept Metab Digest & Reprod, London, England

来源：

GUT | 2025年 / 74卷 / 05期

关键词：

INFLAMMATORY BOWEL DISEASE; COLORECTAL CANCER; ULCERATIVE COLITIS; CANCER PREVENTION; GENETIC INSTABILITY; DNA ANEUPLOIDY; COLORECTAL-CANCER; CHROMOSOMAL INSTABILITY; FIELD CANCERIZATION; CLONAL EXPANSIONS; SHORT TELOMERES; CROHNS-DISEASE; SURVEILLANCE; MUTATIONS; CYTOMETRY;

D O I：

10.1136/gutjnl-2024-333353

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background The risk of developing advanced neoplasia (AN; colorectal cancer and/or high-grade dysplasia) in ulcerative colitis (UC) patients with a low-grade dysplasia (LGD) lesion is variable and difficult to predict. This is a major challenge for effective clinical management. Objective We aimed to provide accurate AN risk stratification in UC patients with LGD. We hypothesised that the pattern and burden of somatic genomic copy number alterations (CNAs) in LGD lesions could predict future AN risk. Design We performed a retrospective multicentre validated case-control study using n=270 LGD samples from n=122 patients with UC. Patients were designated progressors (n=40) if they had a diagnosis of AN in the similar to 5 years following LGD diagnosis or non-progressors (n=82) if they remained AN-free during follow-up. DNA was extracted from the baseline LGD lesion, low-coverage whole genome sequencing performed and data processed to detect CNAs. Survival analysis was used to evaluate CNAs as predictors of future AN risk. Results CNA burden was significantly higher in progressors than non-progressors (p=2x10(-6) in discovery cohort) and was a very significant predictor of AN risk in univariate analysis (OR=36; p=9x10(-7)), outperforming existing clinical risk factors such as lesion size, shape and focality. Optimal risk prediction was achieved with a multivariate model combining CNA burden with the known clinical risk factor of incomplete LGD resection. Within-LGD lesion genetic heterogeneity did not confound risk prediction. Conclusion Measurement of CNAs in LGD is an accurate predictor of AN risk in inflammatory bowel disease and is likely to support clinical management.

引用

页码：740 / 751

页数：12

共 58 条

[1] From Colitis to Cancer: An Evolutionary Trajectory That Merges Maths and Biology [J].

Al Bakir, Ibrahim ;

Curtius, Kit ;

Graham, Trevor A. .

FRONTIERS IN IMMUNOLOGY, 2018, 9

[2]

Andrews S, 2010, Babraham Bioinformatics-FastQC A Quality Control tool for High Throughput Sequence Data

[3]

Andrews S., 2014, BAMQC MAPPED QC ANAL

[4]

[Anonymous], GENOME RES, DOI DOI 10.1101/GR.175141.114

[5] Evolutionary history of human colitis-associated colorectal cancer [J].

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. .

GUT, 2019, 68 (06) :985-995

[6] MUTATIONS IN THE P53 GENE - AN EARLY MARKER OF NEOPLASTIC PROGRESSION IN ULCERATIVE-COLITIS [J].

BRENTNALL, TA ;

CRISPIN, DA ;

RABINOVITCH, PS ;

HAGGITT, RC ;

RUBIN, CE ;

STEVENS, AC ;

BURMER, GC .

GASTROENTEROLOGY, 1994, 107 (02) :369-378

[7]

Butcher S., Apocrita-High Performance Computing Cluster for Queen Mary, DOI [10.5281/zenodo.438045, DOI 10.5281/ZENODO.438045]

[8] Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002) [J].

Cairns, Stuart R. ;

Scholefield, John H. ;

Steele, Robert J. ;

Dunlop, Malcolm G. ;

Thomas, Huw J. W. ;

Evans, Gareth D. ;

Eaden, Jayne A. ;

Rutter, Matthew D. ;

Atkin, Wendy P. ;

Saunders, Brian P. ;

Lucassen, Anneke ;

Jenkins, Paul ;

Fairclough, Peter D. ;

Woodhouse, Christopher R. J. .

GUT, 2010, 59 (05) :666-689

[9] Pan-cancer analysis of whole genomes [J].

Campbell, Peter J. ;

Getz, Gad ;

Korbel, Jan O. ;

Stuart, Joshua M. ;

Jennings, Jennifer L. ;

Stein, Lincoln D. ;

Perry, Marc D. ;

Nahal-Bose, Hardeep K. ;

Ouellette, B. F. Francis ;

Li, Constance H. ;

Rheinbay, Esther ;

Nielsen, G. Petur ;

Sgroi, Dennis C. ;

Wu, Chin-Lee ;

Faquin, William C. ;

Deshpande, Vikram ;

Boutros, Paul C. ;

Lazar, Alexander J. ;

Hoadley, Katherine A. ;

Louis, David N. ;

Dursi, L. Jonathan ;

Yung, Christina K. ;

Bailey, Matthew H. ;

Saksena, Gordon ;

Raine, Keiran M. ;

Buchhalter, Ivo ;

Kleinheinz, Kortine ;

Schlesner, Matthias ;

Zhang, Junjun ;

Wang, Wenyi ;

Wheeler, David A. ;

Ding, Li ;

Simpson, Jared T. ;

O'Connor, Brian D. ;

Yakneen, Sergei ;

Ellrott, Kyle ;

Miyoshi, Naoki ;

Butler, Adam P. ;

Royo, Romina ;

Shorser, Solomon, I ;

Vazquez, Miguel ;

Rausch, Tobias ;

Tiao, Grace ;

Waszak, Sebastian M. ;

Rodriguez-Martin, Bernardo ;

Shringarpure, Suyash ;

Wu, Dai-Ying ;

Demidov, German M. ;

Delaneau, Olivier ;

Hayashi, Shuto .

NATURE, 2020, 578 (7793) :82-+

[10] Integrated clinical and genomic analysis identifies driver events and molecular evolution of colitis-associated cancers [J].

Chatila, Walid K. ;

Walch, Henry ;

Hechtman, Jaclyn F. ;

Moyer, Sydney M. ;

Sgambati, Valeria ;

Faleck, David M. ;

Srivastava, Amitabh ;

Tang, Laura ;

Benhamida, Jamal ;

Ismailgeci, Dorina ;

Campos, Carl ;

Wu, Fan ;

Chang, Qing ;

Vakiani, Efsevia ;

de Stanchina, Elisa ;

Weiser, Martin R. ;

Widmar, Maria ;

Yantiss, Rhonda K. ;

Shah, Manish A. ;

Bass, Adam J. ;

Stadler, Zsofia K. ;

Katz, Lior H. ;

Mellinghoff, Ingo K. ;

Sethi, Nilay S. ;

Schultz, Nikolaus ;

Ganesh, Karuna ;

Kelsen, David ;

Yaeger, Rona .

NATURE COMMUNICATIONS, 2023, 14 (01)

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