{"database":"EGA","file_versions":[],"scores":null,"additional":{"omics_type":["Genomics"],"contact_person":["Jessica Zucman-Rossi"],"full_dataset_link":["https://ega-archive.org/dacs/EGAC00001002924"],"host":["EGA"],"description":["EGA DAC EGAC00001002924"],"repository":["EGA"],"email":["jessica.zucman-rossi@inserm.fr"],"pubmed_abstract":["<h4>Background</h4>Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumours characterised by an activation of the janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway caused by oncogenic activating mutations. However, a subset of IHCA lacks of identified mutation explaining the inflammatory phenotype.<h4>Methods</h4>657 hepatocellular adenomas developed in 504 patients were analysed for gene expression of 17 genes and for mutations in seven genes by sequencing. 22 non-mutated IHCAs were analysed by whole-exome and/or RNA sequencing.<h4>Results</h4>We identified 296 IHCA (45%), 81% of them were mutated in either <i>IL6ST</i> (61%), <i>FRK</i> (8%), <i>STAT3</i> (5%), <i>GNAS</i> (3%) or <i>JAK1</i> (2%). Among non-mutated IHCA, RNA sequencing identified recurrent chromosome rearrangement involving <i>ROS1, FRK</i> or <i>IL6</i> genes. <i>ROS1</i> fusions were identified in 8 IHCA, involving C-terminal part of genes highly expressed in the liver (<i>PLG</i>, <i>RBP4</i>, <i>APOB</i>) fused with exon 33-35 to 43 of <i>ROS1</i> including the tyrosine kinase domain. In two cases a truncated <i>ROS1</i> transcript from exon 36 to 43 was identified. <i>ROS1</i> rearrangements were validated by fluorescence in situ hybridisation (FISH) and led to <i>ROS1</i> overexpression. Among the 5 IHCA with <i>FRK</i> rearrangements, 5 different partners were identified (<i>MIA3</i>, <i>MIA2</i>, <i>LMO7</i>, <i>PLEKHA5, SEC16B</i>) fused to a common region in <i>FRK</i> that included exon 3-8. No overexpression of <i>FRK</i> transcript was detected but the predicted chimeric proteins lacked the auto-inhibitory SH2-SH3 domains. In two IHCA, we identified truncated 3'UTR of <i>IL6</i> associated with overexpression of the transcript.<h4>Conclusion</h4>Recurrent chromosomal alterations involving <i>ROS1</i>, <i>FRK</i> or <i>IL6</i> genes lead to activation of the JAK/STAT pathway in IHCAs.","<h4>Background & aims</h4>Hepatocellular adenomas (HCAs) are benign liver tumors that can be assigned to molecular subtypes based on inactivating mutations in hepatocyte nuclear factor 1A, activating mutations in β-catenin, or activation of inflammatory signaling pathways. We aimed to update the classification system for HCA and associate the subtypes with disease risk factors and complications.<h4>Methods</h4>We analyzed expression levels of 20 genes and sequenced exon regions of 8 genes (HNF1A, IL6ST, CTNNB1, FRK, STAT3, GNAS, JAK1, and TERT) in 607 samples of 533 HCAs from 411 patients, collected from 28 centers mainly in France from 2000 and 2014. We performed gene expression profile, RNA sequence, whole-exome and genome sequence, and immunohistochemical analyses of select samples. Molecular data were associated with risk factors, histopathology, bleeding, and malignant transformation.<h4>Results</h4>Symptomatic bleeding occurred in 14% of the patients (85% of cases were female, median age, 38 years); 7% of the nodules were borderline between HCA and hepatocellular carcinoma, and 3% of patients developed hepatocellular carcinoma from HCA. Based on molecular features, we classified HCA into 8 subgroups. One new subgroup, composed of previously unclassified HCA, represented 4% of HCAs overall and was associated with obesity and bleeding. These tumors were characterized by activation of sonic hedgehog signaling, due to focal deletions that fuse the promoter of INHBE with GLI1. Analysis of genetic heterogeneity among multiple HCAs, from different patients, revealed a molecular subtype field effect; multiple tumors had different mutations that deregulated similar pathways. Specific molecular subtypes of HCA associated with various HCA risk factors, including imbalances in estrogen or androgen hormones. Specific molecular subgroup of HCA with β-catenin and sonic hedgehog activation associated with malignant transformation and bleeding, respectively.<h4>Conclusions</h4>Using sequencing and gene expression analyses, we identified a subgroup of HCA characterized by fusion of the INHBE and GLI1 genes and activation of sonic hedgehog pathway. Molecular subtypes of HCAs associated with different patients' risk factors for HCA, disease progression, and pathology features of tumors. This classification system might be used to select treatment strategies for patients with HCA.","Genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. Analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereas FGF3, FGF4, FGF19 or CCND1 amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (FDA)-approved drugs. In conclusion, we identified risk factor-specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy."],"pubmed_title":["Recurrent chromosomal rearrangements of <i>ROS1</i>, <i>FRK</i> and <i>IL6</i> activating JAK/STAT pathway in inflammatory hepatocellular adenomas.","Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation.","Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets."],"pubmed_authors":["Nault Jean-Charles JC, Couchy Gabrielle G, Balabaud Charles C, Morcrette Guillaume G, Caruso Stefano S, Blanc Jean-Frederic JF, Bacq Yannick Y, Calderaro Julien J, Paradis Valérie V, Ramos Jeanne J, Scoazec Jean-Yves JY, Gnemmi Viviane V, Sturm Nathalie N, Guettier Catherine C, Fabre Monique M, Savier Eric E, Chiche Laurence L, Labrune Philippe P, Selves Janick J, Wendum Dominique D, Pilati Camilla C, Laurent Alexis A, De Muret Anne A, Le Bail Brigitte B, Rebouissou Sandra S, Imbeaud Sandrine S, Bioulac-Sage Paulette P, Letouzé Eric E, Zucman-Rossi Jessica J","Bayard Quentin Q, Caruso Stefano S, Couchy Gabrielle G, Rebouissou Sandra S, Bioulac Sage Paulette P, Balabaud Charles C, Paradis Valerie V, Sturm Nathalie N, de Muret Anne A, Guettier Catherine C, Bonsang Benjamin B, Copie Christiane C, Letouzé Eric E, Calderaro Julien J, Imbeaud Sandrine S, Nault Jean-Charles JC, Zucman-Rossi Jessica J","Schulze Kornelius K, Imbeaud Sandrine S, Letouzé Eric E, Alexandrov Ludmil B LB, Calderaro Julien J, Rebouissou Sandra S, Couchy Gabrielle G, Meiller Clément C, Shinde Jayendra J, Soysouvanh Frederic F, Calatayud Anna-Line AL, Pinyol Roser R, Pelletier Laura L, Balabaud Charles C, Laurent Alexis A, Blanc Jean-Frederic JF, Mazzaferro Vincenzo V, Calvo Fabien F, Villanueva Augusto A, Nault Jean-Charles JC, Bioulac-Sage Paulette P, Stratton Michael R MR, Llovet Josep M JM, Zucman-Rossi Jessica J"],"additional_accession":[]},"is_claimable":false,"name":"FunGeST - Functional Genomics from cancer research to personalized medicine","description":"Data Access Committee EGAC00001002924","dates":{"output":"2025-1-9"},"accession":"EGAC00001002924","cross_references":{"TAXONOMY":["9606"],"pubmed":["31907296","25822088","27939373"],"EGA":["EGAS00001002879","EGAS00001003310","EGAS00001005108","EGAS00001005629","EGAS00001003536","EGAS00001006692","EGAS00001003130","EGAS00001001002","EGAS00001002408","EGAS00001003686","EGAS00001005986","EGAS00001001284","EGAS00001000217","EGAS00001003837","EGAS00001006932","EGAS00001004629","EGAS00001000706","EGAS00001002091","EGAS00001002888","EGAS00001000679","EGAS00001003685","EGAS00001003063","EGAS00001003025","EGAS00001005328","EGAD00001000737","EGAD00001000749","EGAD00001004484","EGAD00001003993","EGAD00001003092","EGAD00001004180","EGAD00001007858","EGAD00001004141","EGAD00001004938","EGAD00001003281","EGAD00001001645","EGAD00001001423","EGAD00001007762","EGAD00001003994","EGAD00001005283","EGAD00001009743","EGAD00001010049","EGAD00001004555","EGAD00001011097","EGAD00001005284","EGAD00001005308","EGAD00001000131","EGAD00001009669","EGAD00001006426","EGAD00001009745","EGAD00001001096"]}}