RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours

被引：28

作者：

Longerich, Thomas ^{[1
,2
]}

Endris, Volker ^{[1
]}

Neumann, Olaf ^{[1
]}

Rempel, Eugen ^{[1
]}

Kirchner, Martina ^{[1
]}

Abadi, Zahra ^{[1
]}

Uhrig, Sebastian ^{[3
,4
]}

Kriegsmann, Mark ^{[1
]}

Weiss, Karl Heinz ^{[2
,5
]}

Breuhahn, Kai ^{[1
]}

Mehrabi, Arianeb ^{[2
,6
]}

Weber, Tim Frederik ^{[2
,7
]}

Wilkens, Ludwig ^{[8
,9
]}

Straub, Beate K. ^{[10
]}

Rosenwald, Andreas ^{[11
,12
]}

Schulze, Falko ^{[13
]}

Brors, Benedikt ^{[4
]}

Froehling, Stefan ^{[14
,15
,16
]}

Pellegrino, Rossella ^{[1
]}

Budczies, Jan ^{[1
]}

Schirmacher, Peter ^{[1
,2
]}

Stenzinger, Albrecht ^{[1
]}

机构：

[1] Univ Klinikum Heidelberg, Inst Pathol, D-69120 Heidelberg, Germany

[2] Univ Klinikum Heidelberg, Liver Canc Ctr Heidelberg, Heidelberg, Germany

[3] Heidelberg Univ, Fac Biosci, Heidelberg, Germany

[4] German Canc Res Ctr, Div Appl Bioinformat, Heidelberg, Germany

[5] Univ Klinikum Heidelberg, Dept Internal Med 5, Heidelberg, Germany

[6] Univ Klinikum Heidelberg, Dept Gen Visceral & Transplantat Surg, Heidelberg, Germany

[7] Univ Hosp Heidelberg, Diagnost & Intervent Radiol, Heidelberg, Germany

[8] Krankenhaus Nordstadt, Inst Pathol, KRH, Hannover, Germany

[9] Hannover Med Sch, Inst Human Genet, Hannover, Germany

[10] Johannes Gutenberg Univ Univ Med, Inst Pathol, Mainz, Germany

[11] Univ Wurzburg, Inst Pathol, Wurzburg, Germany

[12] Comprehens Canc Ctr Mainfranken, Wurzburg, Germany

[13] Klinikum Johann Wolfgang Goethe Univ Frankfurt, Senckenberg Inst Pathol, Frankfurt, Germany

[14] Natl Ctr Tumor Dis NCT Heidelberg, Div Translat Med Oncol, Heidelberg, Germany

[15] German Canc Res Ctr, Heidelberg, Germany

[16] German Canc Consortium DKTK, Heidelberg, Germany

来源：

GUT | 2019年 / 68卷 / 07期

关键词：

R-SPONDIN FAMILY; HEPATOCELLULAR ADENOMA; CLASSIFICATION; MUTATIONS; REGENERATION; ZONATION; CANCER;

D O I：

10.1136/gutjnl-2018-317632

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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

引用

页码：1287 / 1296

页数：10

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