评估代谢产物生物标志物候选物在检测肝硬化患者HCC中的作用

摘要(中文译文)

肝细胞癌（HCC）是癌症最常见的形式，是全球第三大死亡原因。被诊断为HCC的患者预后不佳，主要是由于在疾病的晚期出现症状。此外，传统的生物标志物在HCC的早期检测中显示出不足的疗效，因此强调了识别新的、更有效的生物标志的必要性。本研究旨在评估一组选定的血清生物标志物候选物，用于检测肝硬化（CIRR）患者的HCC。这是通过使用三重四极杆质谱仪对候选物进行有针对性的定量来实现的。使用超高效液相色谱TSQ Altis Plus三重四极杆质谱（UHPLC-MS/MS）通过多反应监测（MRM）分析了50例HCC病例（27例I期HCC）、50例CIRR患者和25名健康对照者的血清样本。通过为每种代谢物创建校准曲线，使用替代矩阵方法对从先前研究中选择的13种内源性代谢物进行绝对定量。统计分析包括带错误发现率（FDR）校正的单变量检验、经临床协变量调整的多变量逻辑回归和受试者操作特征（ROC）曲线。与CIRR相比，HCC中主要涉及氨基酸和胆汁酸代谢的六种代谢产物发生了显著变化，其中四种在I期HCC中与CIRR中也有显著变化。而仅AFP就达到了0.773的AUC ± 0.106 HCC与CIRR的比值为0.804 ± 0.093 I期HCC与CIRR。AFP与六种代谢物组合可提高鉴别能力（AUC 0.870 ± 0.083 0.877 ± 0.059,分别）。在六种代谢产物中，鸟氨酸和脯氨酸在调整了年龄、性别、BMI、MELD评分和HCV状态等混杂因素后仍与HCC相关。靶向代谢组学揭示了HCC中可重复的代谢改变，包括早期疾病；然而，与肝硬化的大量重叠限制了它们的独立诊断实用性。与AFP的整合提供了适度的改善，支持HCC检测的互补多标记方法。

Abstract

Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, ranks as the third leading cause of mortality globally. Patients diagnosed with HCC exhibit a dismal prognosis, mostly due to the emergence of symptoms in the advanced stages of the disease. Moreover, conventional biomarkers demonstrate insufficient efficacy in the early detection of HCC, hence highlighting the need for the identification of novel and more effective biomarkers. This study aims to evaluate a selected panel of serum biomarker candidates for the detection of HCC in patients with liver cirrhosis (CIRR). This is accomplished by targeted quantitation of the candidates using a triple quadrupole mass spectrometer. Serum samples from 50 HCC cases (27 Stage I HCC), 50 patients with CIRR, and 25 healthy controls were analyzed using ultra-high-performance liquid chromatography-TSQ Altis Plus triple quadrupole mass spectrometry (UHPLC-MS/MS) by multiple reaction monitoring (MRM). Absolute quantification of 13 endogenous metabolites selected from previous studies was performed using the surrogate matrix approach by creating calibration curves for each metabolite. Statistical analyses included univariate testing with false discovery rate (FDR) correction, multivariable logistic regression adjusted for clinical covariates, and receiver operating characteristic (ROC) curves. Six metabolites primarily involving amino acid and bile acid metabolism were significantly altered in HCC vs. CIRR, with four of these also significant in Stage I HCC vs. CIRR. While AFP alone achieved AUCs of 0.773 ± 0.106 in HCC vs. CIRR and 0.804 ± 0.093 in Stage I HCC vs. CIRR. The combination of AFP with a six-metabolite panel improved discrimination (AUCs 0.870 ± 0.083 and 0.877 ± 0.059, respectively). Among the six metabolites, ornithine and proline remained associated with HCC after adjusting for confounding factors such as age, sex, BMI, MELD score, and HCV status. Targeted metabolomics reveals reproducible metabolic alterations in HCC, including early-stage disease; however, substantial overlap with cirrhosis limits their independent diagnostic utility. Integration with AFP provides modest improvement, supporting a complementary multi-marker approach for HCC detection.

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