Circulating miR-15b and miR-130b in serum as potential markers for detecting hepatocellular carcinoma: a retrospective cohort study.
Circulating miR-15b and miR-130b in serum as potential markers for detecting hepatocellular carcinoma: a retrospective cohort study.
复制标题
DOI：
10.1136/bmjopen-2012-000825
复制
发表时间：
2012
期刊：
影响因子：
2.9
通讯作者：
Luk JM
中科院分区：
文献类型：
--
作者：
Liu AM;Yao TJ;Wang W;Wong KF;Lee NP;Fan ST;Poon RT;Gao C;Luk JM
血清甲胎蛋白（AFP）是筛查肝细胞癌（HCC）最常用的生物标志物，但约有一半的患者无法检出。因此，我们研究了循环microRNAs（miRNAs）是否可以在HCC检测中优于AFP。回顾性队列研究。中国的两个临床中心。探索阶段包括96名接受原发性根治性肝切除术的HCC患者，验证阶段包括29名B型肝炎携带者，57名HCC患者和30名健康对照。通过实时定量逆转录-PCR测量miRNA的表达。受试者工作特征曲线下面积用于确定使用血清miRNA浓度作为定义HCC的诊断标志物的可行性。使用多变量逻辑回归分析来评估组合的血清miRNA的性能。在探索阶段，对切除的肿瘤/邻近非肿瘤组织的miRNA分析鉴定了在肿瘤中高度表达的miR-15 b、miR-21、miR-130 b和miR-183。这些miRNA在HCC细胞系的培养上清液和患者的血清样品中也是可检测的。值得注意的是，这些血清miRNA在手术后显著减少，表明这些循环miRNA的肿瘤来源。在交叉中心验证研究中，组合的miR-15 b和miR-130 b被证明是HCC检测的分类器，产生0.98的受试者工作特征曲线面积（98.2%灵敏度和91.5%特异性）。分类器在低AFP（<20 ng/ml）的HCC亚组中的检测灵敏度为96.7%。 该分类器还识别了AFP无法检测到的早期HCC病例。联合miR-15 b和miR-130 b分类器是一种具有临床价值的HCC筛查血清生物标志物。超过一半的HCC患者由于诊断时肿瘤分期较晚而不适合接受根治性治疗。长期以来，血清AFP一直被用作HCC筛查的生物标志物，但其敏感性和准确性都很低。循环miRNA在血液中高度稳定，有可能成为有前途的癌症生物标志物。这项研究确定了血清miR-15 b和miR-130 b的组合作为HCC检测的分类器，提供了高灵敏度和准确性。分类器在区分HCC病例与非癌对照方面优于AFP。此外，它还发现了AFP无法检测到的早期肝癌病例。这些发现共同表明，miRNA分类器具有临床价值，可用于HCC筛查计划，这可能会增加HCC患者获得治愈性治疗的机会。所提出的分类器已在包括HCC患者、慢性B型肝炎携带者和健康对照的血清样本的独立队列中得到验证，表明循环miRNA分类器的高阳性预测率，并且可以用作HCC的非侵入性生物标志物。其他变量可能会影响分类器的诊断准确性，例如，丙型肝炎病毒的存在，这也是HCC的风险因素。分类器在丙型肝炎病毒相关HCC中的应用尚待验证。
Serum α-fetoprotein (AFP) is the most commonly used biomarker for screening hepatocellular carcinoma (HCC) but fails to detect about half of the patients. Thus, we investigated if circulating microRNAs (miRNAs) could outperform AFP for HCC detection. A retrospective cohort study. Two clinical centres in China. The exploration phase included 96 patients with HCC who received primary curative hepatectomy, and the validation phase included 29 hepatitis B carriers, 57 patients with HCC and 30 healthy controls. Expression of miRNAs was measured by real-time quantitative reverse transcription–PCR. Areas under receiver operating characteristic curves were used to determine the feasibility of using serum miRNA concentration as a diagnostic marker for defining HCC. A multivariate logistic regression analysis was used to evaluate performances of combined serum miRNAs. In the exploration phase, miRNA profiling on resected tumour/adjacent non-tumour tissues identified miR-15b, miR-21, miR-130b and miR-183 highly expressed in tumours. These miRNAs were also detectable in culture supernatants of HCC cell lines and in serum samples of patients. Remarkably, these serum miRNAs were markedly reduced after surgery, indicating the tumour-derived source of these circulating miRNAs. In a cross-centre validation study, combined miR-15b and miR-130b demonstrated as a classifier for HCC detection, yielding a receiver operating characteristic curve area of 0.98 (98.2% sensitivity and 91.5% specificity). The detection sensitivity of the classifier in a subgroup of HCCs with low AFP (<20 ng/ml) was 96.7%. The classifier also identified early-stage HCC cases that could not be detected by AFP. The combined miR-15b and miR-130b classifier is a serum biomarker with clinical value for HCC screening. More than half of the patients with HCC are not eligible for curative treatments because of the advanced tumour stages at the time of diagnosis. Serum AFP has long been used as a biomarker for HCC screening, but its sensitivity and accuracy are only modest. Circulating miRNAs are highly stable in blood and have a potential to become promising cancer biomarkers. This study identifies combined serum miR-15b and miR-130b as a classifier that provides high sensitivity and accuracy for detection of HCC. The classifier outperformed AFP in discriminating HCC cases from non-cancerous controls. In addition, it identified early-stage HCC cases that could not be detected by AFP. These findings collectively suggest that the miRNA classifier has clinical value and might be used for HCC screening programme, which could increase chances of patients with HCC for curative treatments. The proposed classifier has been validated in an independent cohort of serum samples that includes patients with HCC, chronic hepatitis B carriers and healthy controls, suggesting the high positive predictive rate of the circulating miRNA classifier, and could be used as non-invasive biomarkers for HCC. Other variables may affect the diagnostic accuracy of the classifier, for example, the presence of hepatitis C virus, which is also a risk factor for HCC. The application of the classifier in hepatitis C virus-related HCC is yet to be validated.
登录
查看更多内容
影响因子：
64.8
作者：
Lu, J;Getz, G;Golub, TR
通讯作者：
Golub, TR
影响因子：
9.9
作者：
通讯作者：
--
影响因子：
13.5
作者：
Collier, J;Sherman, M
通讯作者：
Sherman, M
影响因子：
9.8
作者：
Bansal, Ajay;Lee, I. H.;Christenson, L. K.
通讯作者：
Christenson, L. K.
影响因子：
6.5
作者：
Lawrie, Charles H.;Gal, Shira;Harris, Adrian L.
通讯作者：
Harris, Adrian L.