低度发育不良的低覆盖率全基因组测序可有力预测溃疡性结肠炎患者患结直肠癌的风险

Ibrahim Al Bakir, Kit Curtius, George D Cresswell, Heather E Grant, Nadia Nasreddin, Kane Smith, Salpie Nowinski, Qingli Guo, Hayley L Belnoue-Davis, Jennifer Fisher, Theo Clarke, Christopher Kimberley, Maximilian Mossner, Philip D Dunne, Maurice B Loughrey, Ally Speight, James E East, Nicholas A Wright, Manuel Rodriguez-Justo, Marnix Jansen, Morgan Moorghen, Ann-Marie Baker, Simon J Leedham, Ailsa L Hart, Trevor A Graham
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引用次数: 0

摘要

炎症性肠病(IBD)患者罹患结直肠癌(CRC)的风险会增加,而出现低度发育不良(LGD)的患者罹患CRC的风险会急剧增加。然而,目前还没有准确的方法对 LGD 患者进行风险分级,导致癌症风险治疗过度或不足。在这里,我们发现切除的 LGD 病变中的体细胞拷贝数变异(CNAs)可强烈预测未来的癌症发展。我们对122名患者(40名进展期患者,82名非进展期患者,270个LGD区域)进行了回顾性多中心验证病例对照研究。低覆盖率全基因组测序显示,进展期患者的 CNA 负担明显高于非进展期患者(发现队列中的 p=2x10-6),并且在单变量分析中是一个非常重要的 CRC 风险预测因素(几率比 = 36;p=9x10-7),优于现有的临床风险因素,如病变大小、形状和病灶。通过将 CNA 负担与已知的 LGD 未完全切除的临床风险因素相结合的多变量模型,可实现最佳的风险预测。测量 LGD 病变中的 CNA 是一种可靠、低成本且可快速转化的 IBD CRC 风险预测指标,可用于指导管理,从而预防高风险人群的 CRC,同时避免对低风险人群进行不必要的干预。
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Low coverage whole genome sequencing of low-grade dysplasia strongly predicts colorectal cancer risk in ulcerative colitis
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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