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Hepatology. 2017 Dec;66(6):2016-2028. doi: 10.1002/hep.29336. Epub 2017 Oct 30.

Argininosuccinate synthase 1 (ASS1): A marker of unclassified hepatocellular adenoma and high bleeding risk.

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INSERM, UMR1053, BaRITOn Bordeaux Research in Translational Oncology, Bordeaux, France.
Plateforme Protéome, Centre de Génomique Fonctionnelle de Bordeaux, Université de Bordeaux, Bordeaux, France.
Centre de Bioinformatique de Bordeaux, Centre de Génomique Fonctionnelle de Bordeaux, Université de Bordeaux, Bordeaux, France.
Plateforme d'histopathologie, TBM-Core US 005, Bordeaux, France.
INSERM, U1215, Neurocentre Magendie, Bordeaux, France.
LaBRI, CNRS UMR 5800, Université de Bordeaux, Bordeaux, France.
Service de Pathologie, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France.
Service Hépato-Gastroentérologie et oncologie digestive, centre médico-chirurgical Magellan, Hôpital Haut-Lévêque, CHU de Bordeaux, Bordeaux, France.
Oncoprot, INSERM 1053, TBM-Core US 005, Bordeaux, France.


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).

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