肝癌患者血浆BMPR1A和PLAC8基因甲基化水平在预测根治术后早期复发中的意义

The significance of plasma BMPR1A and PLAC8 gene methylation levels in predicting early postoperative recurrence in liver cancer patients

目的探究联合检测血浆中游离BMPR1A、PLAC8基因甲基化预测肝细胞癌术后复发的作用。方法病例系列研究。选取2022年1月至2023年7月中山大学附属第三医院治疗的Ⅰ~Ⅳ期肝细胞癌患者, 入组的所有患者在治疗后1、3、6、9和12个月进行甲胎蛋白(AFP)以及影像学评估检查;同时抽取患者外周血进行血浆循环肿瘤DNA(ctDNA)甲基化检测, 比较患者治疗后血浆中游离BMPR1A和PLAC8基因甲基化检测结果以及传统肿瘤标志物AFP检测的阳性率。采用受试者工作特征(ROC)曲线分析该方法对肝细胞癌复发的预测效能, 并根据游离DNA甲基化结果阳性和阴性, 以及AFP是否大于7 μg/L, 分别将肝细胞癌患者划分为甲基化高风险组(12例)、甲基化低风险组(21例)、AFP高风险组(15例)和AFP低风险组(18例), 进行Kaplan-Meier生存分析。结果联合检测血浆中游离BMPR1A、PLAC8基因甲基化对肝癌复发预测的敏感度为66.7%, 特异度为88.9%, ROC曲线分析BMPR1A、PLAC8基因甲基化检测肝癌复发的曲线下面积为0.770和0.778, AFP为0.522;相比影像学检查, 游离DNA甲基化检测平均可以提前58.3 d检测出肝细胞癌的复发(53.8 d比112.1d)。基于游离DNA甲基化预测的高风险组400 d的无进展生存率为22.2%, 低于低风险组(76.2%, P<0.001)。结论相比于AFP, 检测BMPR1A、PLAC8基因甲基化能更准确地预测肝细胞癌的复发, 可成为一种实用的监测肝癌复发的方法。

Objective To explore the role of combined detection of cell free BMPR1A and PLAC8 gene methylation in plasma in predicting postoperative recurrence of hepatocellular carcinoma.Methods Case series study.Patients with stageⅠ-Ⅳhepatocellular carcinoma who were treated at the Third Affiliated Hospital of Sun-Yat-sen University from January 2022 to July 2023 were selected.All enrolled patients underwent alpha fetoprotein(AFP)and imaging assessments 1 month,3 months,6 months,9 months,and 12 months after treatment.Simultaneously,peripheral blood of patients was extracted for plasma circulating tumor DNA(ctDNA)methylation detection,and the results of free BMPR1A and PLAC8 gene methylation detection in patients′plasma after treatment were compared with the positive rate of traditional tumor marker AFP detection.Draw the receiver operating characteristic curve(ROC)of the subjects to demonstrate the effectiveness of this method in predicting the recurrence of hepatocellular carcinoma.Based on the results of cell free DNA methylation and whether AFP is more than 7μg/L,hepatocellular carcinoma patients were divided into high-risk methylation group(12 cases),low-risk methylation group(21 cases),high-risk AFP group(15 cases),and Kaplan Meier survival analysis was performed on them.Results The sensitivity and specificity of combined detection of free BMPR1A PLAC8 gene methylation in plasma for predicting liver cancer recurrence were 66.7%and 88.9%,respectively.The area under curve(AUC)of BMPR1A PLAC8 gene methylation detection for liver cancer recurrence were 0.770 and 0.778,and the AFP was 0.522 in ROC curve analysis.Compared to imaging examinations,cell free DNA methylation detection can detect the recurrence of hepatocellular carcinoma on average by 58.3 days in advance(53.8 days vs 112.1 days).The progression free survival rate of the high-risk group based on free DNA methylation prediction at 400 days was 22.2%,significantly lower than the low-risk group(76.2%,P<0.001).Conclusion Compared to AFP,detecting the methylation of BMPR1A and PLAC8 genes can predict the recurrence of hepatocellular carcinoma more accurately,making it a practical method for monitoring liver cancer recurrence.