Introduction: Serum α-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-γ-carboxy­pro­thrombin (DCP) are useful biomarkers of hepatocellular carcinoma (HCC). However, associations among molecular characteristics and serum biomarkers are unclear. We analyzed RNA expression and DNA variant data from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) to examine their associations with serum biomarker levels and clinical data. Methods: From 371 TCGA-LIHC patients, we selected 91 seen at 3 institutions in Korea and the USA and measured AFP, AFP-L3, and DCP from preoperatively obtained serum. We conducted an integrative clinical and molecular analysis, focusing on biomarkers, and validated the findings with the remaining 280 patients in the TCGA-LIHC cohort. Results: Patients were categorized into 4 subgroups: elevated AFP or AFP-L3 alone (↑AFPamp;L3), elevated DCP alone (↑DCP), elevation of all 3 biomarkers (elevated levels of all 3 biomarkers [↑All]), and reference range values for all biomarkers (RR). CTNNB1 variants were frequently observed in ↑DCP patients (53.8%) and RR patients (38.5%), but ↑DCP patients with a CTNNB1 variant had worse survival than RR patients. TP53 sequence variants were associated with ↑AFP (30.8%) and ↑DCP (30.8%). The Wnt-β-catenin signaling pathway was activated in the ↑AFPamp;L3, whereas liver-related Wnt signaling was activated in the RR. TGF-β and VEGF signaling were activated in ↑AFPamp;L3, whereas dysregulated bile acid and fatty acid metabolism were dominant in ↑DCP. We validated these findings by showing similar results between the test cohort and the remainder of the TCGA-LIHC cohort. Conclusions: Serum AFP, AFP-L3, and DCP levels can help predict variants in the genetic profile of HCC, especially for TP53 and CTNNB1. These findings may facilitate development of an evidence-based approach to treatment.
Liver Cancer

中文翻译：

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血清肿瘤生物标志物与肝细胞癌综合基因组和临床特征的关联

简介：血清甲胎蛋白 (AFP)、 Lens culinaris凝集素反应性 AFP (AFP-L3) 和 des-γ-羧基凝血酶原 (DCP) 是肝细胞癌 (HCC) 的有用生物标志物。然而，分子特征和血清生物标志物之间的关联尚不清楚。我们分析了癌症基因组图谱肝细胞癌 (TCGA-LIHC) 的 RNA 表达和 DNA 变异数据，以检查它们与血清生物标志物水平和临床数据的关联。方法：从 371 名 TCGA-LIHC 患者中，我们选择了在韩国和美国 3 个机构就诊的 91 名患者，并从术前获得的血清中测量了 AFP、AFP-L3 和 DCP。我们进行了综合临床和分子分析，重点关注生物标志物，并在 TCGA-LIHC 队列中剩余的 280 名患者中验证了这些发现。结果：患者分为 4 个亚组：单独升高的 AFP 或 AFP-L3 (↑AFPamp;L3)、单独升高的 DCP (↑DCP)、所有 3 种生物标志物的升高（所有 3 种生物标志物的水平升高 [↑All]）和所有生物标志物 (RR) 的参考范围值。CTNNB1变异体经常在↑DCP 患者（53.8%）和 RR 患者（38.5%）中观察到，但带有CTNNB1变异体的↑DCP 患者的生存率低于 RR 患者。TP53序列变异与↑AFP（30.8%）和↑DCP（30.8%）相关。Wnt-β-catenin 信号通路在↑AFPamp;L3 中被激活，而肝脏相关的 Wnt 信号在 RR 中被激活。在↑AFPamp;L3中TGF-β和VEGF信号被激活，而在↑DCP中失调的胆汁酸和脂肪酸代谢占主导地位。我们通过在测试队列和 TCGA-LIHC 队列的其余部分之间显示相似的结果来验证这些发现。结论：血清 AFP、AFP-L3 和 DCP 水平有助于预测 HCC 基因谱中的变异，尤其是TP53和CTNNB1。这些发现可能有助于开发基于证据的治疗方法。
肝癌