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

六氯环己烷 突变体 突变 恶性转化 表型 外显子 癌症研究 肝细胞癌 连环素 生物 免疫组织化学 分子生物学 基因 遗传学 Wnt信号通路 免疫学
作者
Sandra Rebouissou,Andrea Franconi,Julien Caldéraro,Éric Letouzé,Sandrine Imbeaud,Camilla Pilati,Jean‐Charles Nault,Gabrielle Couchy,Alexis Laurent,Charles Balabaud,Paulette Bioulac‐Sage,Jessica Zucman–Rossi
出处
期刊:Hepatology [Lippincott Williams & Wilkins]
卷期号:64 (6): 2047-2061 被引量:273
标识
DOI:10.1002/hep.28638
摘要

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.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).
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