Centre de Recherche des Cordeliers, Sorbonne Université, Inserm,Université de Paris, Université Paris 13, Functional Genomics of Solid Tumors laboratory, F-75006 Paris, France.
Service de Pathologie, Hôpital Pellegrin, CHU de Bordeaux, F 33076 Bordeaux, France.
Gut. 2020 Sep;69(9):1667-1676. doi: 10.1136/gutjnl-2019-319790. Epub 2020 Jan 6.
Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumours characterised by an activation of the janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway caused by oncogenic activating mutations. However, a subset of IHCA lacks of identified mutation explaining the inflammatory phenotype.
657 hepatocellular adenomas developed in 504 patients were analysed for gene expression of 17 genes and for mutations in seven genes by sequencing. 22 non-mutated IHCAs were analysed by whole-exome and/or RNA sequencing.
We identified 296 IHCA (45%), 81% of them were mutated in either (61%), (8%), (5%), (3%) or (2%). Among non-mutated IHCA, RNA sequencing identified recurrent chromosome rearrangement involving or genes. fusions were identified in 8 IHCA, involving C-terminal part of genes highly expressed in the liver (, , ) fused with exon 33-35 to 43 of including the tyrosine kinase domain. In two cases a truncated transcript from exon 36 to 43 was identified. rearrangements were validated by fluorescence in situ hybridisation (FISH) and led to overexpression. Among the 5 IHCA with rearrangements, 5 different partners were identified (, , , ) fused to a common region in that included exon 3-8. No overexpression of transcript was detected but the predicted chimeric proteins lacked the auto-inhibitory SH2-SH3 domains. In two IHCA, we identified truncated 3'UTR of associated with overexpression of the transcript.
Recurrent chromosomal alterations involving , or genes lead to activation of the JAK/STAT pathway in IHCAs.
炎症性肝细胞腺瘤（IHCA）是一种良性肝肿瘤，其特征是由于致癌激活突变导致 janus 激酶（JAK）/信号转导和转录激活因子（STAT）通路的激活。然而，亚组 IHCA 缺乏可解释炎症表型的明确突变。
分析了 504 例患者中 657 个肝细胞腺瘤的 17 个基因的基因表达和 7 个基因的测序突变。通过全外显子组和/或 RNA 测序分析了 22 个非突变 IHCA。
我们鉴定了 296 个 IHCA（45%），其中 61%发生在 、8%发生在 、5%发生在 、3%发生在 或 2%发生在 中突变。在非突变 IHCA 中，RNA 测序鉴定出涉及 或 基因的常染色体重排。在 8 个 IHCA 中鉴定出 融合，涉及在肝脏中高表达的基因（ 、 、 ）的 C 末端与包括酪氨酸激酶结构域的 基因的外显子 33-35 到 43 融合。在两个病例中，鉴定出从外显子 36 到 43 的截断 转录本。FISH 验证了 重排，并导致 过表达。在 5 个具有 重排的 IHCA 中，鉴定出 5 个不同的伴侣（ 、 、 、 ）与 中包含外显子 3-8 的共同区域融合。未检测到 转录本的过表达，但预测的嵌合蛋白缺乏自动抑制的 SH2-SH3 结构域。在两个 IHCA 中，我们鉴定出与转录本过表达相关的截断 3'UTR 的 。
涉及 、 或 基因的反复染色体改变导致 IHCA 中 JAK/STAT 通路的激活。
