ASS1 Overexpression: A Hallmark of Sonic Hedgehog Hepatocellular Adenomas; Recommendations for Clinical Practice
ASS1 Overexpression: A Hallmark of Sonic Hedgehog Hepatocellular Adenomas; Recommendations for Clinical Practice
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DOI：
10.1002/hep4.1514
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发表时间：
2020-06-01
影响因子：
5.1
通讯作者：
Saltel, Frederic
中科院分区：
文献类型：
--
作者：
Sala, Margaux;Gonzales, Delphine;Saltel, Frederic
直到最近，10%的肝细胞腺瘤（HCA）仍然未分类（UHCA）。在UHCA中，音刺猬HCA（shHCA）通过融合抑制素β E链的启动子与GLI 1的局灶性缺失来定义。前列腺素D2合酶被提议作为免疫标记物。与此同时，我们以前的工作使用蛋白质组学分析表明，大多数UHCA构成一个同质亚型与过表达的氨基琥珀酸合成酶（ASS 1）。为了阐明ASS 1在HCA分类中的应用并避免对免疫组化染色的误解，本研究的目的是研究（1）shHCA和ASS 1过表达之间的联系以及（2）ASS 1过表达对诊断的临床相关性。在波尔多系列的UHCA病例中进行了分子、蛋白质组和免疫组化分析。临床病理特征，包括ASS 1免疫组化标记，分析了一个大型的国际系列的67例。通过分子分析研究，15例病例中ASS 1过表达和shHCA亚组重叠，确立ASS 1过表达为shHCA的标志。此外，ASS 1免疫标记物优于前列腺素D2合成酶，仅在22例shHCAs中的7例中发现阳性。在67例UHCA病例中，58例（85.3%）过表达ASS 1，4例ASS 1阴性，5例ASS 1无贡献。蛋白质组学分析的情况下进行可疑的解释ASS 1过表达，特别是对活检，可以支持解释这样的情况。ASS1过表达是已知具有高出血风险的shHCA的特异性标志。因此，ASS 1是HCA分类和临床诊断的额外工具。
Until recently, 10% of hepatocellular adenomas (HCAs) remained unclassified (UHCA). Among the UHCAs, the sonic hedgehog HCA (shHCA) was defined by focal deletions that fuse the promoter of Inhibin beta E chain with GLI1. Prostaglandin D2 synthase was proposed as immunomarker. In parallel, our previous work using proteomic analysis showed that most UHCAs constitute a homogeneous subtype associated with overexpression of argininosuccinate synthase (ASS1). To clarify the use of ASS1 in the HCA classification and avoid misinterpretations of the immunohistochemical staining, the aims of this work were to study (1) the link between shHCA and ASS1 overexpression and (2) the clinical relevance of ASS1 overexpression for diagnosis. Molecular, proteomic, and immunohistochemical analyses were performed in UHCA cases of the Bordeaux series. The clinico-pathological features, including ASS1 immunohistochemical labeling, were analyzed on a large international series of 67 cases. ASS1 overexpression and the shHCA subgroup were superimposed in 15 cases studied by molecular analysis, establishing ASS1 overexpression as a hallmark of shHCA. Moreover, the ASS1 immunomarker was better than prostaglandin D2 synthase and only found positive in 7 of 22 shHCAs. Of the 67 UHCA cases, 58 (85.3%) overexpressed ASS1, four cases were ASS1 negative, and in five cases ASS1 was noncontributory. Proteomic analysis performed in the case of doubtful interpretation of ASS1 overexpression, especially on biopsies, can be a support to interpret such cases. ASS1 overexpression is a specific hallmark of shHCA known to be at high risk of bleeding. Therefore, ASS1 is an additional tool for HCA classification and clinical diagnosis.