CTNNB1突变的基因型与表型相关性揭示了与肝肿瘤进展相关的不同β-catenin活性。,Hepatology

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CTNNB1突变的基因型与表型相关性揭示了与肝肿瘤进展相关的不同β-catenin活性。
Hepatology ( IF 12.9 ) Pub Date : 2016-05-15 , DOI: 10.1002/hep.28638
Sandra Rebouissou _{1,

2,

3,

4} , Andrea Franconi _{1,

2,

3,

4} , Julien Calderaro _{1,

2,

3,

4,

5} , Eric Letouzé _{1,

2,

3,

4} , Sandrine Imbeaud _{1,

2,

3,

4} , Camilla Pilati _{1,

2,

3,

4} , Jean-Charles Nault _{1,

2,

3,

4,

6} , Gabrielle Couchy _{1,

2,

3,

4} , Alexis Laurent _{7,

8} , Charles Balabaud _{9,

10} , Paulette Bioulac-Sage _{9,

10,

11} , Jessica Zucman-Rossi _{1,

2,

3,

4,

12}

Affiliation

Inserm, UMR-1162, Functional Genomics of Solid Tumors, Equipe labellisée Ligue Contre le Cancer, Paris, France.
University of Paris Descartes, Sorbonne Paris Cité, Labex Immuno-oncology, Paris, France.
University of Paris Diderot, Sorbonne Paris Cité, University Institute of Hematology, Paris, France.
University of Paris 13, Sorbonne Paris Cité, Saint-Denis, France.
Public Hospitals of Paris, Department of Pathology, CHU Henri Mondor, Créteil, France.
Public Hospitals of Paris, University hospital of Paris-Seine Saint-Denis, Site Jean Verdier, Cancerology unit, Department of Hepatology, Bondy, France.
Public Hospitals of Paris, Department of Digestive and Hepatobiliary Surgery, CHU Henri Mondor, Créteil, France.
INSERM U955 Henri Mondor Hospital University of Paris-Est Créteil, France.
Inserm, UMR-1053, Bordeaux, France.
University of Bordeaux, Bordeaux, France.
Hospital of Bordeaux, Pellegrin Hospital, Department of Pathology, Bordeaux, France.
Public Hospitals of Paris, European Hospital Georges Pompidou, Paris, France.

激活β-catenin的CTNNB1突变是肝细胞癌（HCC）和腺瘤（HCA）中的常见体细胞事件，尤其与恶性转化风险相关。我们旨在了解CTNNB1突变类型，肿瘤表型与恶性转化中ß-catenin活化水平之间的关系。为此，在220个HCA，373个HCC和17个临界HCA / HCC病变中分析了CTNNB1突变谱。通过定量逆转录酶聚合酶链反应和免疫组化（IHC）评估肿瘤中β-catenin活化水平，通过TOP-Flash测定法评估纤维素中的β-catenin活化水平。总体而言，与腺瘤相比，β-catenin活性在恶性突变肿瘤中更高，这与HCC和HCA中不同的CTNNB1突变谱有关。在良性肿瘤中我们定义了与特定突变相关的ß-catenin激活的三个水平：（1）S45，K335和N387突变导致弱激活；（2）T41突变与中等活性有关；（3）高活性突变包括ß-TRCP结合位点（D32-S37）的外显子3缺失和氨基酸取代。因此，在体外，K335I和N387K突变体显示出比S33C更低的活性。具有高活性突变的肿瘤表现出强/均质的谷氨酰胺合酶（GS）染色，并与恶性肿瘤有关。相比之下，弱突变体表现出GS染色的异质性，并且在HCA中更为常见，除了在20％的突变HCA和HCC中相似地鉴定出S45突变体之外。然而，在大多数HCC中，弱的S45突变等位基因被复制，导致最终的高β-catenin活性。结论由特定CTNNB1突变和S45等位基因重复驱动的高β-catenin活性与恶性转化有关。因此，应使用精确的IHC标准或突变筛选来鉴定具有S45的HCA和所有高/中度突变体。（Hepatology 2016; 64：2047-2061）。

"点击查看英文标题和摘要"

Genotype-phenotype correlation of CTNNB1 mutations reveals different ß-catenin activity associated with liver tumor progression.

CTNNB1 mutations activating ß-catenin are frequent somatic events in hepatocellular carcinoma (HCC) and adenoma (HCA), particularly associated with a risk of malignant transformation. We aimed to understand the relationship between CTNNB1 mutation types, tumor phenotype, and level of ß-catenin activation in malignant transformation. To this purpose, CTNNB1 mutation spectrum was analyzed in 220 HCAs, 373 HCCs, and 17 borderline HCA/HCC lesions. ß-catenin activation level was assessed in tumors by quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry (IHC), in cellulo by TOP-Flash assay. Overall, ß-catenin activity was higher in malignant mutated tumors, compared to adenomas, and this was related to a different spectrum of CTNNB1 mutations in HCCs and HCAs. In benign tumors, we defined three levels of ß-catenin activation related to specific mutations: (1) S45, K335, and N387 mutations led to weak activation; (2) T41 mutations were related to moderate activity; and (3) highly active mutations included exon 3 deletions and amino acid substitutions within the ß-TRCP binding site (D32-S37). Accordingly, in vitro, K335I and N387K mutants showed a lower activity than S33C. Tumors with highly active mutations demonstrated strong/homogeneous glutamine synthase (GS) staining and were associated with malignancy. In contrast, weak mutants demonstrated heterogeneous pattern of GS staining and were more frequent in HCAs except for the S45 mutants identified similarly in 20% of mutated HCAs and HCCs; however, in most of the HCCs, the weak S45 mutant alleles were duplicated, resulting in a final high ß-catenin activity. CONCLUSION High ß-catenin activity driven by specific CTNNB1 mutations and S45 allele duplication is associated with malignant transformation. Consequently, HCAs with S45 and all high/moderate mutants should be identified with precise IHC criteria or mutation screening. (Hepatology 2016;64:2047-2061).

更新日期：2019-11-01

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