Although an association between the cytochrome P4502D6 (CYP2D6) *10 (100C>T) polymorphism and hepatocellular carcinoma (HCC) is known, the mechanism remains unclear. Here we aimed to explore mechanisms of CYP2D6*10 (100C>T) polymorphism conferring to HCC, and screen markers for HCC. Label-free global proteome profiling with 34 normal livers and peritumor tissue from 61 HCC patients was performed, and angiopoietin-like protein-6 (ANGPTL6) was evaluated in 2 liver samples validation cohorts and 2 blood specimens validation cohorts. We found a significantly decreased frequency of TT in HCC patients which reduced HCC susceptibility by 69.2% and was accompanied by lowered enzymatic activity for CYP2D6. Proteomic analysis revealed 1342 differentially expressed proteins (DEPs) that were associated with HCC and 88 DEPs were identified as 100 TT-related proteins, likely underlying the susceptibility to HCC. Twenty-two upregulated DEPs and 66 downregulated DEPs were mainly related to lipid metabolism and the extracellular matrix, respectively. High ANGPTL6 was associated with a higher risk to HCC and worse prognosis. ANGPTL6 was both an independent risk factor and an independent prognostic factor for HCC and exhibited strong potential for predicting HCC occurrence, with comparable AUC values and higher sensitivity compared with alpha-fetoprotein. The TT genotype-associated decreased risk of HCC appears to be related to lowered CYP2D6 activity and altered protein expression in the tumor microenvironment, and ANGPTL6 is a promising new diagnostic and prognostic biomarker for HCC. Our findings reveal new mechanistic insights for polymorphisms related to HCC risk and provide avenues for screening for HCC.

中文翻译：

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使用蛋白质组学鉴定具有 CYP2D6*10 多态性的肝细胞癌机制并将 ANGPTL6 鉴定为新的诊断和预后生物标志物

尽管已知细胞色素 P4502D6 (CYP2D6) *10 (100C>T) 多态性与肝细胞癌 (HCC) 之间存在关联，但其机制仍不清楚。在这里，我们旨在探索 CYP2D6*10 (100C>T) 多态性导致 HCC 的机制，并筛选 HCC 的标志物。对来自 61 名 HCC 患者的 34 个正常肝脏和肿瘤周围组织进行了无标记的全局蛋白质组分析，并在 2 个肝脏样本验证队列和 2 个血液样本验证队列中评估了血管生成素样蛋白 6 (ANGPTL6)。我们发现 HCC 患者的 TT 频率显着降低，这使 HCC 易感性降低了 69.2%，并伴随着 CYP2D6 的酶活性降低。蛋白质组学分析揭示了 1342 种与 HCC 相关的差异表达蛋白 (DEP)，88 种 DEP 被鉴定为 100 种 TT 相关蛋白，可能是对 HCC 易感性的基础。22 个上调的 DEP 和 66 个下调的 DEP 分别主要与脂质代谢和细胞外基质有关。高 ANGPTL6 与更高的 HCC 风险和更差的预后相关。ANGPTL6 既是 HCC 的独立危险因素，又是独立的预后因素，并显示出预测 HCC 发生的强大潜力，与甲胎蛋白相比具有可比的 AUC 值和更高的敏感性。TT 基因型相关的 HCC 风险降低似乎与肿瘤微环境中 CYP2D6 活性降低和蛋白质表达改变有关，ANGPTL6 是一种很有前途的新型 HCC 诊断和预后生物标志物。我们的研究结果揭示了与 HCC 风险相关的多态性的新机制见解，并为筛查 HCC 提供了途径。