肝细胞肝癌肿瘤标志物诊断的新进展

Advances in tumour markers for diagnosis of hepatocellular carcinoma

中国疾病预防控制中心数据显示,肝癌位居我国恶性肿瘤死因第2位,是死亡率较高的恶性肿瘤。肝癌具有早期诊断困难(约50%漏诊)、恶性程度高、异质性强及进展迅速等特点,早期诊断可提升治疗效果,延长患者生存期。肝癌的主要病理类型为肝细胞肝癌(hepatocellular carcinoma,HCC),其肿瘤标志物包括甲胎蛋白(α-fetoprotein,AFP)、维生素K缺乏或拮抗剂Ⅱ诱导的凝血酶原(protein induced by vitamin K deficiency or antagonist-Ⅱ,PIVKA-Ⅱ)、α-L-岩藻糖苷酶(α-L-fucosidase,AFU)等,检测简单且高效,但由于HCC的异质性,部分患者的标志物水平未出现异常,52%的小型HCC(<3 cm)患者为AFP阴性,影响HCC诊断的准确率。一些新型肿瘤标志物已被发现,包括循环肿瘤细胞(circulating tumour cell,CTC)、循环游离核酸(包括循环游离DNA(circulating cell-free DNA,cfDNA)和微小RNA(microRNA,miRNA)以及外泌体等。90.81%的CTC阳性HCC患者(包括早期疾病患者),在随访3~5个月后可检测到非常小的HCC结节,表明CTC与HCC特征高度相关,术后监测CTC水平可在临床检测到复发结节出现之前预测HCC复发;cfDNA可作为HCC早期诊断的有效工具,而检测ctDNA内的突变可指导靶向治疗;miRNA可作为诊断疾病和监测疾病进展、预后情况的生物标志物;联合检测AFP与lncRNAs Panel(包含3种循环外泌体来源的长链非编码RNA,即ENSG00000248932.1、ENST00000440688.1、ENST00000457302.2)显示出比单独检测AFP更高的灵敏度和特异度(曲线下面积为0.910和0.408),可预测HCC的发生并动态监测HCC的转移。但这类新型肿瘤标志物仍具有一定的局限性,如由于这类标志物通常以较低水平存在,可能会导致较高的假阴性,并且缺乏标准化的分析前变量和分析变量,在稳定性方面具有局限性。这类肿瘤标志物目前仍不建议独立用于HCC的早期筛查、监测或是在临床上大规模应用,仅可作为传统诊断方法的补充。本文将对近年来肿瘤标志物在HCC诊断中的研究进展进行综述,总结传统肿瘤标志物(AFP、PIVKA-Ⅱ和AFU等)效能,介绍新型肿瘤标志物(CTC、cfDNA、ctDNA、miRNA和外泌体等)的研究进展及临床应用,并对未来提升HCC诊断准确率进行展望。

According to the data from the Chinese Centre for Disease Control and Prevention,the liver cancer ranks second among malignant tumour deaths in China,with a high mortality rate.Liver cancer is characterized by difficult of early diagnosis(about 50%of patients missed),high malignant level,strong heterogeneity,and rapid progression.Early diagnosis can help patients seize the best chance for treatment,reduce the damage to the body,improve the treatment effect,and prolong survival.The main pathological type of liver cancer is hepatocellular carcinoma(HCC).Commonly used clinical tumour markers for HCC include α-fetoprotein(AFP),protein induced by vitamin K deficiency or antagonist-Ⅱ(PIVKA-Ⅱ),a-L-fucosidase(AFU),etc.,which are simple and efficient.However,due to the heterogeneity of liver cancer,the marker levels in some patients were not abnormal,and 52%of HCC patients with small tumours(<3 cm)were AFP-negative,which affected the diagnostic accuracy of HCC.Therefore,some novel tumour markers have been discovered,including circulating tumour cells(CTCs),circulating cell-free nucleic acids[including circulating cell-free DNA(cfDNA)and microRNAs(miRNAs)],and exosomes.It revealed that 90.81%of CTC positive HCC patients(including early disease patients)can detect very small HCC nodules after 3-5 months of follow-up,indicating a high correlation between CTC and HCC characteristics.Postoperative monitoring of CTC levels can predict HCC recurrence before clinical detection of recurrent nodules;cfDNA can serve as an effective tool for early diagnosis of HCC,and detecting mutations in ctDNA can guide targeted therapy;miRNA can serve as a biomarker for diagnosing diseases and monitoring disease progression and prognosis;The joint detection of AFP and lncRNAs panel(including three circulating exosome sources of long chain non coding RNAs:ENSG00000248932.1,ENST000000440688.1,ENST000000457302.2)showed higher sensitivity and specificity than the single detection of AFP(AUC:0.910 and 0.408),which can predict the occurrence of HCC and dynamically monitor HCC metastasis.However,these new tumour markers still have some limitations such as high false-negative rate at low levels,and limitation in stability due to the lack of standardized pre-analytical variables and analytical variables.These tumour markers are still not recommended to be used independently for early screening,monitoring or large-scale clinical application of HCC,and can only be used as a supplement to traditional diagnostic methods.This article reviewed the research progress of tumour markers in the diagnosis of HCC in recent years,summarized the efficacy of traditional tumour markers(AFP,PIVKA-Ⅱ.and AFU,etc.),introduced the research progress and clinical application of new tumour markers(CTC,cfDNA,ctDNA,miRNA and exosomes,etc.),and looked forward to improving the accuracy of HCC diagnosis in the future.