INSERM, UMR1053, BaRITOn Bordeaux Research in Translational Oncology, Bordeaux, France.
Plateforme Protéome, Centre de Génomique Fonctionnelle de Bordeaux, Université de Bordeaux, Bordeaux, France.
Hepatology. 2017 Dec;66(6):2016-2028. doi: 10.1002/hep.29336. Epub 2017 Oct 30.
Hepatocellular adenomas (HCAs) are rare benign tumors divided into three main subgroups defined by pathomolecular features, HNF1A (H-HCA), mutated β-catenin (b-HCA), and inflammatory (IHCA). In the case of unclassified HCAs (UHCAs), which are currently identified by default, a high risk of bleeding remains a clinical issue. The objective of this study was to explore UHCA proteome with the aim to identify specific biomarkers. Following dissection of the tumoral (T) and nontumoral (NT) tissue on formalin-fixed, paraffin-embedded HCA tissue sections using laser capture methodology, we performed mass spectrometry analysis to compare T and NT protein expression levels in H-HCA, IHCA, b-HCA, UHCA, and focal nodular hyperplasia. Using this methodology, we searched for proteins which are specifically deregulated in UHCA. We demonstrate that proteomic profiles allow for discriminating known HCA subtypes through identification of classical biomarkers in each HCA subgroup. We observed specific up-regulation of the arginine synthesis pathway associated with overexpression of argininosuccinate synthase (ASS1) and arginosuccinate lyase in UHCA. ASS1 immunohistochemistry identified all the UHCA, of which 64.7% presented clinical bleeding manifestations. Interestingly, we demonstrated that the significance of ASS1 was not restricted to UHCA, but also encompassed certain hemorrhagic cases in other HCA subtypes, particularly IHCA.
ASS1 + HCA combined with a typical hematoxylin and eosin stain aspect defined a new HCA subgroup at a high risk of bleeding. (Hepatology 2017;66:2016-2028).
肝细胞腺瘤（HCA）是罕见的良性肿瘤，根据病理分子特征分为三个主要亚组，分别为 HNF1A（H-HCA）、突变β-catenin（b-HCA）和炎症（IHCA）。对于未分类的 HCA（UHCA），目前默认通过这种方式进行识别，其仍存在高出血风险的临床问题。本研究的目的是探索 UHCA 蛋白质组，以确定特异性生物标志物。采用激光捕获技术对福尔马林固定、石蜡包埋的 HCA 组织切片的肿瘤（T）和非肿瘤（NT）组织进行解剖后，我们进行了质谱分析，以比较 H-HCA、IHCA、b-HCA、UHCA 和局灶性结节性增生中 T 和 NT 的蛋白表达水平。使用这种方法，我们寻找在 UHCA 中特异性下调的蛋白。我们证明蛋白质组图谱可以通过鉴定每种 HCA 亚组中的经典生物标志物来区分已知的 HCA 亚型。我们观察到精氨酸合成途径的特异性上调，与 UHCA 中精氨酸合成酶（ASS1）和精氨酸琥珀酸裂解酶的过表达相关。ASS1 免疫组化鉴定了所有的 UHCA，其中 64.7%的 UHCA 存在临床出血表现。有趣的是，我们证明 ASS1 的意义不仅限于 UHCA，还包括其他 HCA 亚型中某些出血病例，特别是 IHCA。
ASS1+HCA 结合典型的苏木精和伊红染色外观定义了一个具有高出血风险的新的 HCA 亚组。（Hepatology 2017;66:2016-2028）。
