RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours
RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours
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DOI：
10.1136/gutjnl-2018-317632
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发表时间：
2019-07-01
期刊：
影响因子：
24.5
通讯作者：
Stenzinger, Albrecht
中科院分区：
文献类型：
--
作者：
Longerich, Thomas;Endris, Volker;Stenzinger, Albrecht
目的 我们旨在鉴定可在功能上替代 β-连环蛋白激活的肝细胞腺瘤 (HCA) 和肝细胞癌 (HCC) 中 CTNNB1 突变的遗传改变。 设计 使用免疫组织化学对大型 HCA (n=185) 和 HCC (n=468) 队列进行分类。 CTNNB1 基因的突变状态是在 β-连环蛋白激活的 HCA (b-HCA) 和至少具有中度核 CTNNB1 积累的 HCC 中确定的。使用超深测序来表征 CTNNB1 野生型和 β-连环蛋白激活的 HCA 和 HCC。对 HCA 亚型进行了表达谱分析。 结果 检测到由染色体 8q23.1 上 46.4 kb 微缺失引起的顶板特异性 spondin 2 (RSPO2) 基因重排，作为 β-连环蛋白激活的 HCA 的新形态分子驱动因素。 RSPO2 融合阳性 HCA 显示 RSPO2 蛋白的上调、β-连环蛋白的核积累以及 β-连环蛋白靶基因的转录激活，表明 Wingless 型 MMTV 整合位点家族 (WNT) 信号传导的激活。结构和细胞学异型性以及间质侵入表明其中一个 RSPO2 重排的 b-HCA 发生了恶性转化。在慢性肝病背景下形成的三种 β-连环蛋白激活的 HCC 中也观察到了 RSPO2 基因重排。人类端粒酶逆转录酶启动子的突变（已知可驱动 CTNNB1 突变的 HCA 恶性转化）似乎对于 RSPO2 重排的 HCA 和 HCC 来说是可有可无的。 结论 RSPO2 基因重排导致 HCA 和 HCC 中 WNT 信号通路的致癌激活，代表了 b-HCA 发展的另一种机制，并可能驱动恶性转化 无需额外 TERT 启动子的转化
Objective We aimed at the identification of genetic alterations that may functionally substitute for CTNNB1 mutation in beta-catenin-activated hepatocellular adenomas (HCAs) and hepatocellular carcinoma (HCC).Design Large cohorts of HCA (n=185) and HCC (n=468) were classified using immunohistochemistry. The mutational status of the CTNNB1 gene was determined in beta-catenin-activated HCA (b-HCA) and HCC with at least moderate nuclear CTNNB1 accumulation. Ultradeep sequencing was used to characterise CTNNB1wildtype and beta-catenin-activated HCA and HCC. Expression profiling of HCA subtypes was performed.Results A roof plate-specific spondin 2 (RSPO2) gene rearrangement resulting from a 46.4 kb microdeletion on chromosome 8q23.1 was detected as a new morphomolecular driver of beta-catenin-activated HCA. RSPO2 fusion positive HCA displayed upregulation of RSPO2 protein, nuclear accumulation of beta-catenin and transcriptional activation of beta-catenin-target genes indicating activation of Wingless-Type MMTV Integration Site Family (WNT) signalling. Architectural and cytological atypia as well as interstitial invasion indicated malignant transformation in one of the RSPO2 rearranged b-HCAs. The RSPO2 gene rearrangement was also observed in three beta-catenin-activated HCCs developing in context of chronic liver disease. Mutations of the human telomerase reverse transcriptase promoter-known to drive malignant transformation of CTNNB1-mutated HCA-seem to be dispensable for RSPO2 rearranged HCA and HCC.Conclusion The RSPO2 gene rearrangement leads to oncogenic activation of the WNT signalling pathway in HCA and HCC, represents an alternative mechanism for the development of b-HCA and may drive malignant transformation without additional TERT promoter