Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours

Rebouissou, Sandra; Amessou, Mohamed; Couchy, Gabrielle; Poussin, Karine; Imbeaud, Sandrine; Pilati, Camilla; Izard, Tina; Balabaud, Charles; Bioulac‐Sage, Paulette; Zucman‐Rossi, Jessica

doi:10.1038/nature07475

Cited by 430 publications

(418 citation statements)

References 36 publications

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“…15,17 A combination of gp130 alterations and b-catenin mutation is likely in these cases leading to the activation of both pathways. 20 The diffuse glutamine synthetase pattern in these cases is different from focal nodular hyperplasia map-like pattern, which often shows sparing of hepatocytes around the fibrous septa.…”

Section: Discussionmentioning

confidence: 81%

“…15,17,18 Inflammatory hepatocellular adenomas are frequently characterized by in-frame deletions of the interleukin-6 signaling transducer gp130 protein or mutations of activator of transcription 3 (STAT3). 19,20 This leads to constitutive activation of the interleukin-6 pathway and expression of acute phase reactants, serum amyloid-associated protein and C-reactive protein.…”

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confidence: 99%

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Diagnostic utility and limitations of glutamine synthetase and serum amyloid-associated protein immunohistochemistry in the distinction of focal nodular hyperplasia and inflammatory hepatocellular adenoma

et al. 2014

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Inflammatory hepatocellular adenoma can show overlapping histological features with focal nodular hyperplasia, including inflammation, fibrous stroma, and ductular reaction. Expression of serum amyloidassociated protein in inflammatory hepatocellular adenoma and map-like pattern of glutamine synthetase in focal nodular hyperplasia can be helpful in this distinction, but the pitfalls and limitations of these markers have not been established. Morphology and immunohistochemistry were analyzed in 54 inflammatory hepatocellular adenomas, 40 focal nodular hyperplasia, and 3 indeterminate lesions. Morphological analysis demonstrated that nodularity, fibrous stroma, dystrophic blood vessels, and ductular reaction were more common in focal nodular hyperplasia, while telangiectasia, hemorrhage, and steatosis were more common in inflammatory hepatocellular adenoma, but there was frequent overlap of morphological features. The majority of inflammatory hepatocellular adenomas demonstrated perivascular and/or patchy glutamine synthetase staining (73.6%), while the remaining cases had diffuse (7.5%), negative (3.8%), or patchy pattern of staining (15%) that showed subtle differences from the classic map-like staining pattern and was designated as pseudo map-like staining. Positive staining for serum amyloid-associated protein was seen in the majority of inflammatory hepatocellular adenomas (92.6%) and in the minority of focal nodular hyperplasia (17.5%). The glutamine synthetase staining pattern was map-like in 90% of focal nodular hyperplasia cases, with the remaining 10% of cases showing pseudo map-like staining. Three cases were labeled as indeterminate and showed focal nodular hyperplasia-like morphology but lacked map-like glutamine synthetase staining pattern; these cases demonstrated a patchy pseudo map-like glutamine synthetase pattern along with the expression of serum amyloid-associated protein. Our results highlight the diagnostic errors that can be caused by variant patterns of staining with glutamine synthetase and serum amyloid-associated protein in inflammatory hepatocellular adenoma and focal nodular hyperplasia.

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Section: Discussionmentioning

confidence: 81%

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confidence: 99%

Diagnostic utility and limitations of glutamine synthetase and serum amyloid-associated protein immunohistochemistry in the distinction of focal nodular hyperplasia and inflammatory hepatocellular adenoma

et al. 2014

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“…Immunohistochemistry showed CCL20 expression in macrophages but not in endothelial cells (30). In monocytes/macrophages, CCL20 is a hypoxia-inducible gene as illustrated by ischemic/hypoxic transcriptome studies (31,32), in which it constitutes an important mechanism to promote recruitment of specific leukocyte subsets at pathologic sites. Thus, in SOS, hypoxia possibly triggers CCL20 expression.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling Provides Insights into Pathways of Oxaliplatin-Related Sinusoidal Obstruction Syndrome in Humans

Rubbia‐Brandt

Tauzin

Brézault

et al. 2011

Molecular Cancer Therapeutics

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Sinusoidal obstruction syndrome (SOS; formerly veno-occlusive disease) is a well-established complication of hematopoietic stem cell transplantation, pyrrolizidine alkaloid intoxication, and widely used chemotherapeutic agents such as oxaliplatin. It is associated with substantial morbidity and mortality. Pathogenesis of SOS in humans is poorly understood. To explore its molecular mechanisms, we used Affymetrix U133 Plus 2.0 microarrays to investigate the gene expression profile of 11 human livers with oxaliplatin-related SOS and compared it to 12 matched controls. Hierarchical clustering analysis showed that profiles from SOS and controls formed distinct clusters. To identify functional networks and gene ontologies, data were analyzed by the Ingenuity Pathway Analysis Tool. A total of 913 genes were differentially expressed in SOS: 613 being upregulated and 300 downregulated. Reverse transcriptase-PCR results showed excellent concordance with microarray data. Pathway analysis showed major gene upregulation in six pathways in SOS compared with controls: acute phase response (notably interleukin 6), coagulation system (Serpine1, THBD, and VWF), hepatic fibrosis/hepatic stellate cell activation (COL3a1, COL3a2, PDGF-A, TIMP1, and MMP2), and oxidative stress. Angiogenic factors (VEGF-C) and hypoxic factors (HIF1A) were upregulated. The most significant increase was seen in CCL20 mRNA. In conclusion, oxaliplatin-related SOS can be readily distinguished according to morphologic characteristics but also by a molecular signature. Global gene analysis provides new insights into mechanisms underlying chemotherapy-related hepatotoxicity in humans and potential targets relating to its diagnosis, prevention, and treatment. Activation of VEGF and coagulation (vWF) pathways could partially explain at a molecular level the clinical observations that bevacizumab and aspirin have a preventive effect in SOS.

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“…2,5 The third group of hepatocellular adenoma, namely inflammatory adenoma (about 50% of all hepatocellular adenomas), harbor somatic gain-offunction mutations in either IL6ST, FRK, JAK1, STAT3, or GNAS genes activating the interleukin-6/ JAK/STAT pathway. 3,6,8,9 They are histologically characterized by sinusoidal dilation, inflammatory infiltrates, and dystrophic vessels often surrounded by fibrotic tissue. An immunohistochemical panel has been developed to allow pathological identification of all three hepatocellular adenoma subgroups and inflammatory adenomas are characterized by an overexpression of the C-reactive and serum amyloid A proteins in tumor hepatocytes.…”

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confidence: 99%

Inflammatory hepatocellular adenomas developed in the setting of chronic liver disease and cirrhosis

et al. 2016

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Hepatocellular adenoma is considered to occur exclusively in non-fibrotic livers. It is a heterogeneous entity and a molecular classification is now widely accepted. The most frequent hepatocellular adenoma subtype, namely inflammatory adenoma, harbor somatic activating mutations of genes involved in the interleukin-6 pathway that lead to high C-reactive protein and serum amyloid A expression. The aim of our study was to investigate a series of benign hepatocellular neoplasms developed on cirrhotic livers and characterized by an unequivocal histological diagnosis. We performed a clinical, pathological, and molecular study of 10 benign hepatocellular neoplasms developed in three patients with cirrhosis. Markers allowing hepatocellular adenoma classification were assessed by quantitative real-time PCR and immunohistochemistry. Samples were sequenced for CTNNB1, HNF1A, IL6ST, GNAS, STAT3, and TERT (promoter) mutations. A control series of 32 classical macronodules developed in cirrhosis related to various etiologies was screened by immunohistochemistry and gene sequencing. The three patients had cirrhosis related to metabolic syndrome and/or alcohol intake; two had a single tumor, while the third developed more than 30 lesions. Microscopic examination showed welldifferentiated neoplasms sharing features with inflammatory adenoma including inflammatory infiltrates, sinusoidal dilatation, and dystrophic vessels. Sequencing revealed classical hotspot somatic mutations (IL6ST, n = 8; STAT3, n = 1; and GNAS, n = 1) known to be responsible for IL-6/JAK/STAT pathway activation. Two classical high-grade macronodules demonstrated high serum amyloid A and/or C-reactive protein expression, without gene mutations. Altogether, our findings support the existence of rare inflammatory adenoma developed in cirrhosis.

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Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours

Cited by 430 publications

References 36 publications

Diagnostic utility and limitations of glutamine synthetase and serum amyloid-associated protein immunohistochemistry in the distinction of focal nodular hyperplasia and inflammatory hepatocellular adenoma

Diagnostic utility and limitations of glutamine synthetase and serum amyloid-associated protein immunohistochemistry in the distinction of focal nodular hyperplasia and inflammatory hepatocellular adenoma

Gene Expression Profiling Provides Insights into Pathways of Oxaliplatin-Related Sinusoidal Obstruction Syndrome in Humans

Inflammatory hepatocellular adenomas developed in the setting of chronic liver disease and cirrhosis

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