Department of Pathology, Nanfang Hospital and Basic Medical College, Southern Medical University, Guangzhou, PR China.
Department of Pathology, General Hospital of Southern Theater Command, People's Liberation Army of China, Guangzhou, PR China.
J Pathol. 2023 Apr;259(4):376-387. doi: 10.1002/path.6047. Epub 2023 Jan 28.
For stage III colorectal cancer (CRC) patients with a high risk of recurrence, intensified adjuvant chemotherapy can improve overall survival. We aimed to develop a circulating tumor DNA (ctDNA) methylation marker model for predicting the relapse risk of stage III CRC patients. Differentially methylated markers identified between 53 normal mucosa samples and 165 CRC tissue samples, as well as between plasma samples from 75 stage I/II (early-stage) CRC patients and 55 stage IV (late-stage) CRC patients, were analyzed using Student's t-tests. The overlapping methylation markers shared by plasma and tissue samples were used to establish a methylation marker model to evaluate the tumor burden in the peripheral blood of CRC patients using the random forest method. This model was verified in the validation cohort (n = 44) and then applied to predict recurrence risk in 50 stage III CRC patients and monitor the clinical disease course in serial samples from four CRC patients. We built a five-marker-based ctDNA methylation model that had high sensitivity (84.21%) and specificity (84%) in identifying late-stage CRC in a validation cohort containing 24 stage I/II CRC patients and 20 stage IV CRC patients. The model achieved high sensitivity (87.5%) and specificity (94.12%) in predicting tumor relapse in an independent cohort of 50 stage III CRC patients and could be an independent recurrence risk factor for stage III patients [Hazard ratio (HR), 60.4; 95% confidence interval (CI): 7.68-397; p = 9.73e-5]. Analysis of serial blood samples of CRC showed that the model could monitor disease relapse earlier than imaging examination and serum carcinoembryonic antigen (CEA) and so may provide an opportunity for the early adjustment of therapeutic strategies. Moreover, the model could potentially monitor the clinical course and treatment response dynamically. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
对于有复发高风险的 III 期结直肠癌（CRC）患者，强化辅助化疗可以提高总生存率。我们旨在开发一种循环肿瘤 DNA（ctDNA）甲基化标记物模型，用于预测 III 期 CRC 患者的复发风险。使用学生 t 检验分析了在 53 个正常黏膜样本和 165 个 CRC 组织样本之间以及在 75 个 I/II 期（早期）CRC 患者和 55 个 IV 期（晚期）CRC 患者的血浆样本之间差异甲基化标记物。使用随机森林法分析血浆和组织样本共有的重叠甲基化标记物，以建立一种甲基化标记物模型，用于评估 CRC 患者外周血中的肿瘤负担。该模型在验证队列（n=44）中进行了验证，然后应用于 50 名 III 期 CRC 患者的复发风险预测，并在 4 名 CRC 患者的连续样本中监测临床疾病过程。我们构建了一个基于 5 个标志物的 ctDNA 甲基化模型，该模型在包含 24 名 I/II 期 CRC 患者和 20 名 IV 期 CRC 患者的验证队列中识别晚期 CRC 的敏感性（84.21%）和特异性（84%）较高。该模型在 50 名 III 期 CRC 患者的独立队列中预测肿瘤复发的敏感性（87.5%）和特异性（94.12%）较高，并且可能是 III 期患者的独立复发风险因素[风险比（HR），60.4；95%置信区间（CI）：7.68-397；p=9.73e-5]。对 CRC 连续血样的分析表明，该模型可以比影像学检查和血清癌胚抗原（CEA）更早地监测疾病复发，因此可能为早期调整治疗策略提供机会。此外，该模型可能具有动态监测临床过程和治疗反应的潜力。
