SOX9 Expression in Colorectal Adenomas Improves Surveillance Colonoscopy Risk Stratification in a Bowel Screening Population

Sara Samir Foad Al-Badran, Christopher Bigley, Mark Johnstone, Aula Ammar, Alexander Winton, Jennifer Hay, Jean Quinn, Jakub Jawny, Ditte Andersen, Natalie Fisher, Philip Dunne, Noori Maka, Gerard Lynch, Stephen McSorley, Joanne Edwards, on behalf of the INCISE Collaborative
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Abstract

Objectives Adenomas are known precursors to colorectal cancer (CRC). Current UK post-polypectomy surveillance guidelines use polyp size, numbers, and histology to stratify the risk of patients developing metachronous polyps or CRC. However, these risk guidelines suffer from poor predictive value, often leading to under/over surveillance. Design Adenomas removed from 1257 patients at bowel screening colonoscopy were retrospectively identified to investigate mutational profile and protein expression trends associated with the detection of metachronous polyps or CRC. The presence or absence of metachronous polyps or CRC was recorded 6 months to 6 years after index polypectomy. Results APC and KRAS were the most mutated genes in these patients (87% and 34% respectively), and both were significantly co-occurring with the 6th most mutated gene SOX9 (17% co-occurring with APC, p=0.047; 23% co-occurring with KRAS, p=0.012). High SOX9 cytoplasmic expression was significantly associated with the detection of metachronous polyps or CRC (HR 1.543, p=0.001) and improved high risk stratification when combined with BSG2020 guidelines versus guidelines alone (HR 2.626, p<0.0001). High cytoplasmic SOX9 alone and in combination with current guidelines was an independent predictor of metachronous polyps or CRC according to various regression models. This was validated in an independent test dataset, where high cytoplasmic expression was significantly associated with the detection of metachronous polyps or CRC (HR 1.654, p=0.012) and enhanced risk stratification when combined with BSG2020 guidelines versus guidelines alone (HR 2.473, p=0.0018). Conclusion High cytoplasmic SOX9 expression within adenomas is associated with shorter time to detection of metachronous polyps or CRC.
结肠直肠腺瘤中的 SOX9 表达可改善肠道筛查人群的监视结肠镜检查风险分层
目标已知腺瘤是结直肠癌 (CRC) 的前兆。英国目前的息肉切除术后监测指南使用息肉大小、数量和组织学对患者罹患异位息肉或 CRC 的风险进行分层。然而,这些风险指南的预测价值较低,常常导致监测不足或过度。设计回顾性地鉴定了1257名患者在肠道筛查结肠镜检查中切除的腺瘤,以研究与检测出变异息肉或CRC相关的突变概况和蛋白表达趋势。结果APC和KRAS是这些患者中突变最多的基因(分别占87%和34%),这两个基因与第6大突变基因SOX9显著共存(17%与APC共存,p=0.047;23%与KRAS共存,p=0.012)。SOX9 细胞质高表达与检测出隐性息肉或 CRC 显著相关(HR 1.543,p=0.001),与 BSG2020 指南相比,结合 BSG2020 指南可改善高风险分层(HR 2.626,p<0.0001)。根据不同的回归模型,细胞质 SOX9 偏高单独或与现行指南结合使用均可独立预测远期息肉或 CRC。这一点在一个独立的测试数据集中得到了验证,细胞质高表达与检测出变异息肉或 CRC 显著相关(HR 1.654,p=0.012),当与 BSG2020 指南相结合时,风险分层能力比单独与 BSG2020 指南相结合时更强(HR 2.473,p=0.0018)。
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