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).

HCCS

Malignant Transformation

10.1002/hep.28638

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Data from Long Noncoding RNA NIHCOLE Promotes Ligation Efficiency of DNA Double-Strand Breaks in Hepatocellular Carcinoma

Juan P. Unfried Mikel Marín-Baquero Ángel Rivera-Calzada Nerea Razquin Eva M. Martín-Cuevas

<div>AbstractLong noncoding RNAs (lncRNA) are emerging as key players in cancer as parts of poorly understood molecular mechanisms. Here, we investigated lncRNAs that play a role in hepatocellular carcinoma (HCC) and identified NIHCOLE, a novel lncRNA induced in HCC with oncogenic potential and a role in the ligation efficiency of DNA double-stranded breaks (DSB). NIHCOLE expression was associated with poor prognosis and survival of HCC patients. Depletion of NIHCOLE from HCC cells led to impaired proliferation and increased apoptosis. NIHCOLE deficiency led to accumulation of DNA damage due to a specific decrease in the activity of the nonhomologous end-joining (NHEJ) pathway of DSB repair. DNA damage induction in NIHCOLE-depleted cells further decreased HCC cell growth. NIHCOLE was associated with DSB markers and recruited several molecules of the Ku70/Ku80 heterodimer. Further, NIHCOLE putative structural domains supported stable multimeric complexes formed by several NHEJ factors including Ku70/80, APLF, XRCC4, and DNA ligase IV. NHEJ reconstitution assays showed that NIHCOLE promoted the ligation efficiency of blunt-ended DSBs. Collectively, these data show that NIHCOLE serves as a scaffold and facilitator of NHEJ machinery and confers an advantage to HCC cells, which could be exploited as a targetable vulnerability.Significance:This study characterizes the role of lncRNA NIHCOLE in DNA repair and cellular fitness in HCC, thus implicating it as a therapeutic target.See related commentary by Barcena-Varela and Lujambio, p. 4899</div>

10.1158/0008-5472.c.6512958

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Hepatocellular adenomas: Magnetic resonance imaging features as a function of molecular pathological classification

Hepatology (2008)

H. Laumonier Paulette Bioulac‐Sage Camille Laurent Jessica Zucman‐Rossi Charles Balabaud

Abstract Hepatocellular adenomas (HCAs) are a group of benign tumors forming three molecular pathological subgroups: (1) hepatocyte nuclear factor 1α (HNF-1α)–inactivated, (2) β-catenin–activated, and (3) inflammatory. Some HCAs present both β-catenin activation and inflammation. We analyzed magnetic resonance imaging (MRI) data for correlations between features on imaging and pathological classification of HCAs. We included 50 cases for which pathology specimens were classified into three groups based on immunohistochemical staining. Two characteristic MRI profiles were identified corresponding to HNF-1α–inactivated and inflammatory HCAs. Fifteen HCAs were HNF-1α–inactivated. The corresponding lesions showed (1) diffuse signal dropout on T1-weighted chemical shift sequence due to steatosis, (2) isosignal or slight hypersignal on T2-weighted (T2W) images, and (3) moderate enhancement in the arterial phase, with no persistent enhancement in the portal venous and delayed phases. For the diagnosis of HNF-1α–inactivated HCA, the positive predictive value of homogeneous signal dropout on chemical shift images was 100%, the negative predictive value was 94.7%, the sensitivity was 86.7%, and the specificity was 100%. Twenty-three HCAs were inflammatory and showed (1) an absence or only focal signal dropout on chemical shift sequence; (2) marked hypersignal on T2W sequences, with a stronger signal in the outer part of the lesions, correlating with sinusoidal dilatation areas; and (3) strong arterial enhancement, with persistent enhancement in the portal venous and delayed phases. Marked hypersignal on T2W sequences associated with delayed persistent enhancement had a positive predictive value of 88.5%, a negative predictive value of 84%, a sensitivity of 85.2%, and a specificity of 87.5% for the diagnosis of inflammatory HCA. Conclusion: HNF-1α–mutated HCAs and inflammatory HCAs were associated with specific MRI patterns related to diffuse fat repartition and sinusoidal dilatation, respectively. (Hepatology 2008.)

Steatosis

10.1002/hep.22417

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From the Editor’s desk...

Journal of Hepatology (2016)

Richard Moreau Ramón Bataller Thomas Berg Jessica Zucman‐Rossi Rajiv Jalan

Hepatitis C

Liver function

10.1016/j.jhep.2016.07.041

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Supplementary Table 7 from Immune Profiling of Combined Hepatocellular- Cholangiocarcinoma Reveals Distinct Subtypes and Activation of Gene Signatures Predictive of Response to Immunotherapy

Công Trung Nguyễn Stefano Caruso Pascale Maillé Aurélie Beaufrère Jérémy Augustin

Supplementary Table 7: Difference in gene expression between Immune Low 1 (IL1) and Immune Low 2 (IL2) subgroups in the validation dataset (n=20, Coulouarn et al. Carcinogenesis. 2012) (33).

Profiling (computer programming)

10.1158/1078-0432.22484217

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From the Editor’s desk....

Journal of Hepatology (2019)

Richard Moreau Ramón Bataller Thomas Berg Sophie Lotersztajn Jessica Zucman‐Rossi

Desk

10.1016/j.jhep.2018.12.020

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Supplementary Data from Immune Profiling of Combined Hepatocellular- Cholangiocarcinoma Reveals Distinct Subtypes and Activation of Gene Signatures Predictive of Response to Immunotherapy