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

医学 结直肠癌 内科学 发育不良 优势比 肿瘤科 溃疡性结肠炎 炎症性肠病 队列 癌症 疾病 逻辑回归
作者
Ibrahim Al Bakir,Kit Curtius,George D. Cresswell,Heather E. Grant,Nadia Nasreddin,NULL AUTHOR_ID,Salpie Nowinski,NULL AUTHOR_ID,NULL AUTHOR_ID,Jennifer Fisher,NULL AUTHOR_ID,NULL AUTHOR_ID,NULL AUTHOR_ID,NULL AUTHOR_ID,NULL AUTHOR_ID,NULL AUTHOR_ID,NULL AUTHOR_ID,Nicholas A. Wright,NULL AUTHOR_ID,Marnix Jansen,Morgan Moorghen,Ann‐Marie Baker,NULL AUTHOR_ID,Ailsa Hart,NULL AUTHOR_ID
标识
DOI:10.1101/2024.07.08.24309811
摘要

Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal cancer (CRC), and this risk increases dramatically in those who develop low-grade dysplasia (LGD). However, there is currently no accurate way to risk-stratify patients with LGD, leading to both over- and under-treatment of cancer risk. Here we show that the burden of somatic copy number alterations (CNAs) within resected LGD lesions strongly predicts future cancer development. We performed a retrospective multi-centre validated case-control study of n=122 patients (40 progressors, 82 non-progressors, 270 LGD regions). Low coverage whole genome sequencing revealed CNA burden was significantly higher in progressors than non-progressors (p=2x10 -6 in discovery cohort) and was a very significant predictor of CRC risk in univariate analysis (odds ratio = 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. The measurement of CNAs in LGD lesions is a robust, low-cost and rapidly translatable predictor of CRC risk in IBD that can be used to direct management and so prevent CRC in high-risk individuals whilst sparing those at low-risk from unnecessary intervention.

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