多组学联合检测可对肝癌高危人群进行有效机会性筛查

Multi-omics combined test performance effectiveness on opportunistic screening of high-risk liver cancer population

目的拟验证一项多组学联合检测在肝癌高危人群进行肝癌早筛的性能。方法在真实世界环境下前瞻性筛选173例肝癌高危患者,最后入组164例患者。所有患者均行B超、甲胎蛋白(AFP)和HCCscreen检测。HCCscreen检测是一项合并多基因甲基化、TP53/TERT/CTNNB1突变、AFP和异常凝血酶原(PIVKA-Ⅱ)的多组学肝癌早筛检测。计数资料使用χ^(2)检验、校正χ^(2)检验或Fisher精确概率法比较率的差异;等级资料使用非参数检验(Mann-Whitney)法比较两组数据间的差异。结果HCCscreen检测对肝癌的筛查灵敏度为100%,对肝癌及癌前疾病的筛查灵敏度为93.8%,阳性预测值34.1%,阴性预测值99.2%,曲线下面积(AUC)为0.89。平行检测的AFP、AFP+B超和甲基化+突变的灵敏度/特异度及AUC分别为31.3%/88.5%(AUC=0.78)、56.3%/88.2%(AUC=0.86)和81.3%/82.4%(AUC=0.84)。同时,疾病严重程度与甲基化+突变评分、HCCscreen评分或阳性检出率存在显著相关性。虽然AFP血清水平与甲基化+突变或HCCscreen评分之间没有显著相关性,但甲基化+突变评分与HCCscreen评分之间存在显著的线性相关性(r=0.73,P<0.001)。结论在真实世界机会性筛查条件下,HCCscreen显示出对肝癌高危人群筛查高灵敏度,可有效发现肝癌及癌前疾病,其表现优于AFP及AFP+B超。HCCscreen有潜力成为优于现有筛查方法的肝癌高危人群的有效筛查工具。

Objective To validate the performance of a multi-omics combined test for early screening of high-risk liver cancer populations.Methods 173 high-risk patients with liver cancer were prospectively screened in a real-world setting,and 164 cases were finally enrolled.B-ultrasound,alpha-fetoprotein(AFP),and HCC screens were conducted in all patients.A multi-omics early screening test was performed for liver cancer in combination with multi-gene methylation,TP53/TERT/CTNNB1 mutations,AFP,and abnormal prothrombin(PIVKA-Ⅱ).Differences in rates were compared using the chi-square test,adjusted chi-square test,or Fisher's exact probability method for count data.A non-parametric rank test(Mann-Whitney)was used to compare the differences between the two groups of data.Results The HCCscreen detection had a sensitivity of 100% for liver cancer screening,93.8%for liver cancer and precancerous diseases,34.1%for positive predictive value,99.2%for negative predictive value,and 0.89 for an area under the curve(AUC).Parallel detection of AFP,AFP+B-ultrasound,and methylation+mutation had a sensitivity/specificity and AUC of 31.3%/88.5%(AUC=0.78),56.3%/88.2%(AUC=0.86),and 81.3%/82.4%(AUC=0.84).At the same time,the disease severity range was significantly correlated with the methylation+mutation score,HCCscreen score,or positive detection rate(PDR).There was no significant correlation between AFP serum levels and methylation+mutation or HCCscreen scores,while there was a significant linear correlation between methylation+mutation scores and HCCscreen scores(r=0.73,P<0.001).Conclusion In real-world settings,HCCscreen shows high sensitivity for screening opportunistic,high-risk liver cancer populations.Furthermore,it may efficaciously detect liver cancer and precancerous diseases,with superior performance to AFP and AFP+ultrasound.Hence,HCCscreen has the potential to become an effective screening tool that is superior to existing screening methods for high-risk liver cancer populations.