Publications by authors named "Jessica Zucman-Rossi"

250 Publications

Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma.

Genome Med 2021 Jul 14;13(1):113. Epub 2021 Jul 14.

Centre de Recherche des Cordeliers, Inserm UMRS-1138, Sorbonne Université, Université de Paris, Functional Genomics of Solid Tumors, Paris, France.

Background: Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples.

Methods: Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic, or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed.

Results: Sequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed the contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment, were observed and led to a switch from a hot to a cold immune profile in three patients.

Conclusions: This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic, and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support the need for multi-sampling for the implementation of molecular-based precision medicine.
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http://dx.doi.org/10.1186/s13073-021-00931-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281651PMC
July 2021

MicroRNAs Targeting HIF-2α, VEGFR1 and/or VEGFR2 as Potential Predictive Biomarkers for VEGFR Tyrosine Kinase and HIF-2α Inhibitors in Metastatic Clear-Cell Renal Cell Carcinoma.

Cancers (Basel) 2021 Jun 21;13(12). Epub 2021 Jun 21.

Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, 3000 Leuven, Belgium.

Metastatic clear-cell renal cell carcinoma (m-ccRCC) is characterized by increased hypoxia-induced factor (HIF)-2α and vascular endothelial growth factor receptor (VEGFR)-dependent angiogenesis through loss of function of the von Hippel-Lindau protein. VEGFR tyrosine kinase inhibitors (VEGFR-TKIs) are a cornerstone of m-ccRCC treatment, and new treatments targeting HIF-2α are currently under investigation. However, predictive biomarkers for these treatments are lacking. In this retrospective cohort study including 109 patients treated with VEGFR-targeted therapies as first-line treatment, we aimed to study the possible predictive function of microRNAs (miRNAs) targeting HIF-2α, VEGFR1 and VEGFR2. We selected miRNAs inversely correlated with HIF-2α, VEGFR1 and/or VEGFR2 expression and with predicted target sites in the respective genes and subsequently studied their impact on therapeutic outcomes. We identified four miRNAs (miR-34c-5p, miR-221-3p, miR-222-3p and miR-3529-3p) inversely correlated with VEGFR1 and/or VEGFR2 expression and associated with tumor shrinkage and progression-free survival (PFS) upon treatment with VEGFR-TKIs, highlighting the potential predictive value of these miRNAs. Moreover, we identified three miRNAs (miR-185-5p, miR-223-3p and miR-3529-3p) inversely correlated with HIF-2α expression and associated with tumor shrinkage and PFS upon treatment with VEGFR-TKIs. These three miRNAs can have a predictive value not only upon treatment with VEGFR-TKIs but possibly also upon treatment with the upcoming HIF-2α inhibitor belzutifan.
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http://dx.doi.org/10.3390/cancers13123099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235409PMC
June 2021

Genomics of Viral Hepatitis-Associated Liver Tumors.

J Clin Med 2021 Apr 22;10(9). Epub 2021 Apr 22.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France.

Virus-related liver carcinogenesis is one of the main contributors of cancer-related death worldwide mainly due to the impact of chronic hepatitis B and C infections. Three mechanisms have been proposed to explain the oncogenic properties of hepatitis B virus (HBV) infection: induction of chronic inflammation and cirrhosis, expression of HBV oncogenic proteins, and insertional mutagenesis into the genome of infected hepatocytes. Hepatitis B insertional mutagenesis modifies the function of cancer driver genes and could promote chromosomal instability. In contrast, hepatitis C virus promotes hepatocellular carcinoma (HCC) occurrence mainly through cirrhosis development whereas the direct oncogenic role of the virus in human remains debated. Finally, adeno associated virus type 2 (AAV2), a defective DNA virus, has been associated with occurrence of HCC harboring insertional mutagenesis of the virus. Since these tumors developed in a non-cirrhotic context and in the absence of a known etiological factor, AAV2 appears to be the direct cause of tumor development in these patients via a mechanism of insertional mutagenesis altering similar oncogenes and tumor suppressor genes targeted by HBV. A better understanding of virus-related oncogenesis will be helpful to develop new preventive strategies and therapies directed against specific alterations observed in virus-related HCC.
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http://dx.doi.org/10.3390/jcm10091827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122827PMC
April 2021

Integrated genomic analysis identifies driver genes and cisplatin-resistant progenitor phenotype in pediatric liver cancer.

Cancer Discov 2021 Apr 23. Epub 2021 Apr 23.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris

Pediatric liver cancers (PLCs) comprise diverse diseases affecting infants, children and adolescents. Despite overall good prognosis, PLCs display heterogeneous response to chemotherapy. Integrated genomic analysis of 126 pediatric liver tumors showed a continuum of driver mechanisms associated with patient age, including new targetable oncogenes. In 10% of hepatoblastoma patients, all before 3 years old, we identified a mosaic premalignant clonal expansion of cells altered at the 11p15.5 locus. Analysis of spatial and longitudinal heterogeneity revealed an important plasticity between 'Hepatocytic', 'Liver Progenitor' and 'Mesenchymal' molecular subgroups of hepatoblastoma. We showed that during chemotherapy, 'Liver Progenitor' cells accumulated massive loads of cisplatin-induced mutations with a specific mutational signature, leading to the development of heavily mutated relapses and metastases. Drug screening in PLC cell lines identified promising targets for cisplatin-resistant progenitor cells, validated in mouse xenograft experiments. These data provide new insights into cisplatin resistance mechanisms in PLC and suggest alternative therapies.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1809DOI Listing
April 2021

MicroRNAs Possibly Involved in the Development of Bone Metastasis in Clear-Cell Renal Cell Carcinoma.

Cancers (Basel) 2021 Mar 28;13(7). Epub 2021 Mar 28.

Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, 3000 Leuven, Belgium.

Bone metastasis in clear-cell renal cell carcinoma (ccRCC) leads to substantial morbidity through skeletal related adverse events and implicates worse clinical outcomes. MicroRNAs (miRNA) are small non-protein coding RNA molecules with important regulatory functions in cancer development and metastasis. In this retrospective analysis we present dysregulated miRNA in ccRCC, which are associated with bone metastasis. In particular, miR-23a-3p, miR-27a-3p, miR-20a-5p, and miR-335-3p specifically correlated with the earlier appearance of bone metastasis, compared to metastasis in other organs. In contrast, miR-30b-3p and miR-139-3p were correlated with less occurrence of bone metastasis. These miRNAs are potential biomarkers and attractive targets for miRNA inhibitors or mimics, which could lead to novel therapeutic possibilities for bone targeted treatment in metastatic ccRCC.
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http://dx.doi.org/10.3390/cancers13071554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036650PMC
March 2021

DNA Methylation Signatures Reveal the Diversity of Processes Remodeling Hepatocellular Carcinoma Methylomes.

Hepatology 2021 Mar 13. Epub 2021 Mar 13.

Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Université Paris Nord, Functional Genomics of Solid Tumors Laboratory, Equipe Labellisée Ligue Contre le Cancer, Paris, France.

DNA methylation patterns are highly rearranged in hepatocellular carcinomas (HCCs). However, diverse sources of variation are intermingled in cancer methylomes, precluding the precise characterization of underlying molecular mechanisms. We developed a computational framework (methylation signature analysis with independent component analysis [MethICA]), leveraging independent component analysis (ICA) to disentangle the diverse processes contributing to DNA methylation changes in tumors. Applied to a collection of 738 HCCs, MethICA unraveled 13 stable methylation components (MCs) preferentially active in specific chromatin states, sequence contexts, and replication timings. These included signatures of general processes associated with gender and age but also new signatures related to specific driver events and molecular subgroups. Catenin beta 1 (CTNNB1) mutations were major modulators of methylation patterns in HCC, characterized by a targeted hypomethylation of transcription factor 7 (TCF7)-bound enhancers in the vicinity of Wnt target genes as well as a widespread hypomethylation of late-replicated partially methylated domains (PMDs). By contrast, demethylation of early-replicated highly methylated domains (HMDs) was a signature of replication stress, leading to an extensive hypomethylator phenotype in cyclin (CCN)-activated HCC. Inactivating mutations of the chromatin remodeler AT-rich interactive domain-containing protein 1A (ARID1A) were associated with epigenetic silencing of differentiation-promoting transcriptional networks, also detectable in cirrhotic liver. Finally, a hypermethylation signature targeting Polycomb-repressed chromatin domains was identified in the G1 molecular subgroup with progenitor features. Conclusion: This study elucidates the diversity of processes remodeling HCC methylomes and reveals the epigenetic and transcriptional impact of driver alterations.
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http://dx.doi.org/10.1002/hep.31796DOI Listing
March 2021

Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma.

Gut 2021 Feb 9. Epub 2021 Feb 9.

Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France

Objective: Infection by HBV is the main risk factor for hepatocellular carcinoma (HCC) worldwide. HBV directly drives carcinogenesis through integrations in the human genome. This study aimed to precisely characterise HBV integrations, in relation with viral and host genomics and clinical features.

Design: A novel pipeline was set up to perform viral capture on tumours and non-tumour liver tissues from a French cohort of 177 patients mainly of European and African origins. Clonality of each integration event was determined with the localisation, orientation and content of the integrated sequence. In three selected tumours, complex integrations were reconstructed using long-read sequencing or Bionano whole genome mapping.

Results: Replicating HBV DNA was more frequently detected in non-tumour tissues and associated with a higher number of non-clonal integrations. In HCC, clonal selection of HBV integrations was related to two different mechanisms involved in carcinogenesis. First, integration of viral enhancer nearby a cancer-driver gene may lead to a strong overexpression of oncogenes. Second, we identified frequent chromosome rearrangements at HBV integration sites leading to cancer-driver genes () alterations at distance. Moreover, HBV integrations have direct clinical implications as HCC with a high number of insertions develop in young patients and have a poor prognosis.

Conclusion: Deep characterisation of HBV integrations in liver tissues highlights new HBV-associated driver mechanisms involved in hepatocarcinogenesis. HBV integrations have multiple direct oncogenic consequences that remain an important challenge for the follow-up of HBV-infected patients.
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http://dx.doi.org/10.1136/gutjnl-2020-323153DOI Listing
February 2021

Plk1, upregulated by HIF-2, mediates metastasis and drug resistance of clear cell renal cell carcinoma.

Commun Biol 2021 02 5;4(1):166. Epub 2021 Feb 5.

Centre Scientifique de Monaco, Biomedical Department, 8 quai Antoine Premier, 98 000, Monaco, Monaco.

Polo-like kinase 1 (Plk1) expression is inversely correlated with survival advantages in many cancers. However, molecular mechanisms that underlie Plk1 expression are poorly understood. Here, we uncover a hypoxia-regulated mechanism of Plk1-mediated cancer metastasis and drug resistance. We demonstrated that a HIF-2-dependent regulatory pathway drives Plk1 expression in clear cell renal cell carcinoma (ccRCC). Mechanistically, HIF-2 transcriptionally targets the hypoxia response element of the Plk1 promoter. In ccRCC patients, high expression of Plk1 was correlated to poor disease-free survival and overall survival. Loss-of-function of Plk1 in vivo markedly attenuated ccRCC growth and metastasis. High Plk1 expression conferred a resistant phenotype of ccRCC to targeted therapeutics such as sunitinib, in vitro, in vivo, and in metastatic ccRCC patients. Importantly, high Plk1 expression was defined in a subpopulation of ccRCC patients that are refractory to current therapies. Hence, we propose a therapeutic paradigm for improving outcomes of ccRCC patients.
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http://dx.doi.org/10.1038/s42003-021-01653-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865059PMC
February 2021

The lncRNA H19-Derived MicroRNA-675 Promotes Liver Necroptosis by Targeting FADD.

Cancers (Basel) 2021 Jan 22;13(3). Epub 2021 Jan 22.

The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Medical Center, Ein Karem, P.O.B. 12000, Jerusalem 9112001, Israel.

The -derived microRNA-675 (miR-675) has been implicated as both tumor promoter and tumor suppressor and also plays a role in liver inflammation. We found that miR-675 promotes cell death in human hepatocellular carcinoma (HCC) cell lines. We show that Fas-associated protein with death domain (FADD), a mediator of apoptotic cell death signaling, is downregulated by miR-675 and a negative correlation exists between miR-675 and FADD expression in mouse models of HCC ( = 0.014) as well as in human samples ( = 0.017). We demonstrate in a mouse model of liver inflammation that overexpression of miR-675 promotes necroptosis, which can be inhibited by the necroptosis-specific inhibitor Nec-1/Nec-1s. miR-675 induces the level of both p-MLKL (Mixed Lineage Kinase Domain-Like Pseudokinase) and RIP3 (receptor-interacting protein 3), which are key signaling molecules in necroptosis, and enhances MLKL binding to RIP3. miR-675 also inhibits the levels of cleaved caspases 8 and 3, suggesting that miR-675 induces a shift from apoptosis to a necroptotic cellular pathway. In conclusion, downregulation of FADD by miR-675 promotes liver necroptosis in response to inflammatory signals. We propose that this regulation cascade can stimulate and enhance the inflammatory response in the liver, making miR-675 an important regulator in liver inflammation and potentially also in HCC.
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http://dx.doi.org/10.3390/cancers13030411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866230PMC
January 2021

Expression of NKG2D ligands is downregulated by β-catenin signalling and associates with HCC aggressiveness.

J Hepatol 2021 Jun 21;74(6):1386-1397. Epub 2021 Jan 21.

Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Team Proliferation Stress and Liver Physiopathology, F-75006 Paris, France. Electronic address:

Background & Aims: The NKG2D system is a potent immunosurveillance mechanism in cancer, wherein the activating NK cell receptor (NKG2D) on immune cells recognises its cognate ligands on tumour cells. Herein, we evaluated the expression of NKG2D ligands in hepatocellular carcinoma (HCC), in both humans and mice, taking the genomic features of HCC tumours into account.

Methods: The expression of NKG2D ligands (MICA, MICB, ULBP1 and ULBP2) was analysed in large human HCC datasets by Fluidigm TaqMan and RNA-seq methods, and in 2 mouse models (mRNA and protein levels) reproducing the features of both major groups of human tumours.

Results: We provide compelling evidence that expression of the MICA and MICB ligands in human HCC is associated with tumour aggressiveness and poor patient outcome. We also found that the expression of ULBP1 and ULBP2 was associated with poor patient outcome, and was downregulated in CTNNB1-mutated HCCs displaying low levels of inflammation and associated with a better prognosis. We also found an inverse correlation between ULBP1/2 expression levels and the expression of β-catenin target genes in patients with HCC, suggesting a role for β-catenin signalling in inhibiting expression. We showed in HCC mouse models that β-catenin signalling downregulated the expression of Rae-1 NKG2D ligands, orthologs of ULBPs, through TCF4 binding.

Conclusions: We demonstrate that the expression of NKG2D ligands is associated with aggressive liver tumorigenesis and that the downregulation of these ligands by β-catenin signalling may account for the less aggressive phenotype of CTNNB1-mutated HCC tumours.

Lay Summary: The NKG2D system is a potent immunosurveillance mechanism in cancer. However, its role in hepatocellular carcinoma development has not been widely investigated. Herein, we should that the expression of NKG2D ligands by tumour cells is associated with a more aggressive tumour subtype.
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http://dx.doi.org/10.1016/j.jhep.2021.01.017DOI Listing
June 2021

Hepatocellular carcinoma.

Nat Rev Dis Primers 2021 01 21;7(1). Epub 2021 Jan 21.

Department of Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Liver cancer remains a global health challenge, with an estimated incidence of >1 million cases by 2025. Hepatocellular carcinoma (HCC) is the most common form of liver cancer and accounts for ~90% of cases. Infection by hepatitis B virus and hepatitis C virus are the main risk factors for HCC development, although non-alcoholic steatohepatitis associated with metabolic syndrome or diabetes mellitus is becoming a more frequent risk factor in the West. Moreover, non-alcoholic steatohepatitis-associated HCC has a unique molecular pathogenesis. Approximately 25% of all HCCs present with potentially actionable mutations, which are yet to be translated into the clinical practice. Diagnosis based upon non-invasive criteria is currently challenged by the need for molecular information that requires tissue or liquid biopsies. The current major advancements have impacted the management of patients with advanced HCC. Six systemic therapies have been approved based on phase III trials (atezolizumab plus bevacizumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab) and three additional therapies have obtained accelerated FDA approval owing to evidence of efficacy. New trials are exploring combination therapies, including checkpoint inhibitors and tyrosine kinase inhibitors or anti-VEGF therapies, or even combinations of two immunotherapy regimens. The outcomes of these trials are expected to change the landscape of HCC management at all evolutionary stages.
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http://dx.doi.org/10.1038/s41572-020-00240-3DOI Listing
January 2021

AICAR and compound C negatively modulate HCC-induced primary human hepatic stellate cell activation in vitro.

Am J Physiol Gastrointest Liver Physiol 2021 04 6;320(4):G543-G556. Epub 2021 Jan 6.

Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom.

Tumor stroma and microenvironment have been shown to affect hepatocellular carcinoma (HCC) growth, with activated hepatic stellate cells (HSC) as a major contributor in this process. Recent evidence suggests that the energy sensor adenosine monophosphate-activated kinase (AMPK) may mediate a series of essential processes during carcinogenesis and HCC progression. Here, we investigated the effect of different HCC cell lines with known or mutations on primary human HSC activation, proliferation, and AMPK activation. We show that conditioned media obtained from multiple HCC cell lines differently modulate human hepatic stellate cell (hHSC) proliferation and hHSC AMPK activity in a paracrine manner. Pharmacological treatment of hHSC with AICAR and Compound C inhibited the HCC-induced proliferation/activation of hHSC through AMPK-dependent and AMPK-independent mechanisms, which was further confirmed using mouse embryonic fibroblasts (MEFs) deficient of both catalytic AMPKα isoforms () and wild type (wt) MEF. Both compounds induced S-phase cell-cycle arrest and, in addition, AICAR inhibited the mTORC1 pathway by inhibiting phosphorylation of 4E-BP1 and S6 in hHSC and wt MEF. Data mining of the Cancer Genome Atlas (TCGA) and the Liver Cancer (LICA-FR) showed that AMPKα1 () and AMPKα2 () expression differed depending on the mutation ( or ), tumor grading, and G1-G6 classification, reflecting the heterogeneity in human HCC. Overall, we provide evidence that AMPK modulating pharmacological agents negatively modulate HCC-induced hHSC activation and may therefore provide a novel approach to target the mutual, tumor-promoting interactions between hHSC and HCC. HCC is marked by genetic heterogeneity and activated hepatic stellate cells (HSC) are considered key players during HCC development. The paracrine effect of different HCC cell lines on the activation of primary hHSC was accompanied by differential AMPK activation depending on the HCC line used. Pharmacological treatment inhibited the HCC-induced hHSC activation through AMPK-dependent and AMPK-independent mechanisms. This heterogenic effect on HCC-induced AMPK activation was confirmed by data mining TCGA and LICA-FR databases.
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http://dx.doi.org/10.1152/ajpgi.00262.2020DOI Listing
April 2021

Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target.

J Hepatol 2021 May 15;74(5):1155-1166. Epub 2020 Dec 15.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France; Functional Genomics of Solid Tumors laboratory, Équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France; Hôpital Européen Georges Pompidou, APHP, F-75015, Paris, France. Electronic address:

Background & Aims: Telomerase activation is the earliest event in hepatocellular carcinoma (HCC) development. Thus, we aimed to elucidate the role of telomere length maintenance during liver carcinogenesis.

Methods: Telomere length was measured in the tumor and non-tumor liver tissues of 1,502 patients (978 with HCC) and integrated with TERT alterations and expression, as well as clinical and molecular (analyzed by genome, exome, targeted and/or RNA-sequencing) features of HCC. The preclinical efficacy of anti-TERT antisense oligonucleotides (ASO) was assessed in vitro in 26 cell lines and in vivo in a xenograft mouse model.

Results: Aging, liver fibrosis, male sex and excessive alcohol consumption were independent determinants of liver telomere attrition. HCC that developed in livers with long telomeres frequently had wild-type TERT with progenitor features and BAP1 mutations. In contrast, HCC that developed on livers with short telomeres were enriched in the non-proliferative HCC class and frequently had somatic TERT promoter mutations. In HCCs, telomere length is stabilized in a narrow biological range around 5.7 kb, similar to non-tumor livers, by various mechanisms that activate TERT expression. Long telomeres are characteristic of very aggressive HCCs, associated with the G3 transcriptomic subclass, TP53 alterations and poor prognosis. In HCC cell lines, TERT silencing with ASO was efficient in highly proliferative and poorly differentiated cells. Treatment for 3 to 16 weeks induced cell proliferation arrest in 12 cell lines through telomere shortening, DNA damage and activation of apoptosis. The therapeutic effect was also obtained in a xenograft mouse model.

Conclusions: Telomere maintenance in HCC carcinogenesis is diverse, and is associated with tumor progression and aggressiveness. The efficacy of anti-TERT ASO treatment in cell lines revealed the oncogenic addiction to TERT in HCC, providing a preclinical rationale for anti-TERT ASO treatment in HCC clinical trials.

Lay Summary: Telomeres are repeated DNA sequences that protect chromosomes and naturally shorten in most adult cells because of the inactivation of the TERT gene, coding for the telomerase enzyme. Here we show that telomere attrition in the liver, modulated by aging, sex, fibrosis and alcohol, associates with specific clinical and molecular features of hepatocellular carcinoma, the most frequent primary liver cancer. We also show that liver cancer is dependent on TERT reactivation and telomere maintenance, which could be targeted through a novel therapeutic approach called antisense oligonucleotides.
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http://dx.doi.org/10.1016/j.jhep.2020.11.052DOI Listing
May 2021

The pro-oncogenic effect of the lncRNA H19 in the development of chronic inflammation-mediated hepatocellular carcinoma.

Oncogene 2021 01 22;40(1):127-139. Epub 2020 Oct 22.

The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

The oncofetal long noncoding RNA (lncRNA) H19 is postnatally repressed in most tissues, and re-expressed in many cancers, including hepatocellular carcinoma (HCC). The role of H19 in carcinogenesis is a subject of controversy. We aimed to examine the role of H19 in chronic inflammation-mediated hepatocarcinogenesis using the Mdr2/Abcb4 knockout (Mdr2-KO) mouse, a well-established HCC model. For this goal, we have generated Mdr2-KO/H19-KO double knockout (dKO) mice and followed spontaneous tumor development in the dKO and control Mdr2-KO mice. Cellular localization of H19 and effects of H19 loss in the liver were determined in young and old Mdr2-KO mice. Tumor incidence and tumor load were both significantly decreased in the liver of dKO versus Mdr2-KO females. The expression levels of H19 and Igf2 were variable in nontumor liver tissues of Mdr2-KO females and were significantly downregulated in most matched tumors. In nontumor liver tissue of aged Mdr2-KO females, H19 was expressed mainly in hepatocytes, and hepatocyte proliferation was increased compared to dKO females. At an early age, dKO females displayed lower levels of liver injury and B-cell infiltration, with higher percentage of binuclear hepatocytes. In human samples, H19 expression was higher in females, positively correlated with cirrhosis (in nontumor liver samples) and negatively correlated with CTNNB1 (beta-catenin) mutations and patients' survival (in tumors). Our data demonstrate that the lncRNA H19 is pro-oncogenic during the development of chronic inflammation-mediated HCC in the Mdr2-KO mouse model, mainly by increasing liver injury and decreasing hepatocyte polyploidy in young mice.
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http://dx.doi.org/10.1038/s41388-020-01513-7DOI Listing
January 2021

A TLR3 Ligand Reestablishes Chemotherapeutic Responses in the Context of FPR1 Deficiency.

Cancer Discov 2021 Feb 12;11(2):408-423. Epub 2020 Oct 12.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Paris, France.

For anthracycline-based chemotherapy to be immunogenic, dying cancer cells must release annexin A1 (ANXA1) that subsequently interacts with the pattern recognition receptor, formyl peptide receptor 1 (FPR1), on the surface of dendritic cells (DC). Approximately 30% of individuals bear loss-of-function alleles of , calling for strategies to ameliorate their anticancer immune response. Here, we show that immunotherapy with a ligand of Toll-like receptor-3, polyinosinic:polycytidylic acid (pIC), restores the deficient response to chemotherapy of tumors lacking ANXA1 developing in immunocompetent mice or those of normal cancers growing in FPR1-deficient mice. This effect was accompanied by improved DC- and T-lymphocyte-mediated anticancer immunity. Of note, carcinogen-induced breast cancers precociously developed in FPR1-deficient mice as compared with wild-type controls. A similar tendency for earlier cancer development was found in patients carrying the loss-of-function allele of . These findings have potential implications for the clinical management of FPR1-deficient patients. SIGNIFICANCE: The loss-of-function variant rs867228 in , harbored by approximately 30% of the world population, is associated with the precocious manifestation of breast, colorectal, esophageal, and head and neck carcinomas. pIC restores deficient chemotherapeutic responses in mice lacking , suggesting a personalized strategy for compensating for the FPR1 defect..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0465DOI Listing
February 2021

Liver adenomatosis and NAFLD developed in the context of hereditary fructose intolerance.

Liver Int 2020 12;40(12):3125-3126

Pathology department, Beaujon University Hospital, AP-HP, Clichy, France.

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http://dx.doi.org/10.1111/liv.14673DOI Listing
December 2020

MicroRNA expression profiles in molecular subtypes of clear-cell renal cell carcinoma are associated with clinical outcome and repression of specific mRNA targets.

PLoS One 2020 11;15(9):e0238809. Epub 2020 Sep 11.

Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.

Clear-cell renal cell carcinomas (ccRCC) can be divided into four transcriptomic subtypes, two of which have a favorable and two an unfavorable prognosis. To assess mechanisms driving these subtypes, we investigated their miRNA expression patterns. miRNAs are master regulators of mRNAs, that are widely deregulated in cancer. Unsupervised clustering in our dataset (n = 128) and The Cancer Genome Atlas (TCGA) validation set identified two distinct miRNA clusters that overlapped with the transcriptomic subtypes, underscoring the validity of these subtypes on a multi-omics level and suggesting a driving role for miRNAs. Discriminatory miRNAs for the favorable subtypes repressed epithelial-to-mesenchymal transition, based on gene set enrichment analysis and target-mRNA expression levels. Strikingly, throughout the entire dataset, miRNAs associated with favorable subtypes were also associated with longer overall survival after diagnosis, and miRNAs associated with unfavorable subtypes with shorter overall survival (Pearson r = -0.54, p<0.0001). These findings indicate a general shift in miRNA expression between more and less aggressive tumors. This adds to current literature, which usually suggests only a small subset of miRNAs as markers of aggressive disease. In conclusion, this study reveals distinct mRNA expression patterns underlying transcriptomic ccRCC-subtypes, whereby miRNAs associated with favorable subtypes counteract epithelial-to-mesenchymal transition. There is a general shift in miRNA expression in ccRCC, between more and less aggressive tumors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238809PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485767PMC
November 2020

Sigma 1 Receptor is Overexpressed in Hepatocellular Adenoma: Involvement of ERα and HNF1α.

Cancers (Basel) 2020 Aug 7;12(8). Epub 2020 Aug 7.

UMRs 1174, University Paris-Saclay, Inserm, 91405 Orsay, France.

Sigma receptor 1 (SigR1) is an endoplasmic reticulum resident integral membrane protein whose functions remain unclear. Although the liver shows the highest expression of SigR1, its role in this organ is unknown. SigR1 is overexpressed in many cancers and its expression is correlated to hormonal status in hormone-dependent cancers. To better understand the role of SigR1 in hepatocytes we focused our work on the regulation of its expression in tumoral liver. In this context, hepatocellular adenomas, benign hepatic tumors associated with estrogen intake are of particular interest. The expression of SigR1 mRNA was assessed in hepatocellular adenoma (HCA) patients using qPCR. The impact of estrogen on the expression of SigR1 was studied in vivo (mice) and in vitro (HepG2 and Huh7 cells). The effect of HNF1α on the expression of SigR1 was studied in vivo by comparing wild type mice to HNF1 knockout mice. Estrogen enhanced SigR1 expression through its nuclear receptor ERα. HNF1α mutated HCA (H-HCA) significantly overexpressed SigR1 compared to all other HCA subtypes. HNF1 knockout mice showed an increase in SigR1 expression. Overexpressing SigR1 in cellular models increases proliferation rate and storage of lipid droplets, which phenocopies the H-HCA phenotype. SigR1 is involved in hepatocyte proliferation and steatosis and may play an important role in the control of the H-HCA phenotype.
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http://dx.doi.org/10.3390/cancers12082213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464972PMC
August 2020

New insights in the management of Hepatocellular Adenoma.

Liver Int 2020 07 11;40(7):1529-1537. Epub 2020 Jun 11.

Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

Hepatocellular adenoma (HCA) are benign liver tumours that may be complicated by haemorrhage or malignant transformation to hepatocellular carcinoma. Epidemiological data are fairly outdated, but it is likely to assume that the incidence has increased over the past decades as HCA are more often incidentally found due to the more widespread use of imaging techniques and the increased incidence of obesity. Various molecular subgroups have been described. Each of these molecular subgroups are defined by specific gene mutations and pathway activations. Additionally, they are all related to specific risk factors and show a various biological behaviour. These molecular subgroups may be identified using immunohistochemistry and molecular characterization. Contrast-enhanced MRI is the recommended imaging modality to analyse patients with suspected hepatocellular adenoma allowing to determine the subtype in up to 80%. Surgical resection remains to be the golden standard in treating HCA, although resection is deemed unnecessary in a large number of cases, as studies have shown that the majority of HCA will regress over time without complications such as haemorrhage or malignant transformation occurring. It is preferable to treat patients with suspected HCA in high volume centres with combined expertise of liver surgeons, hepatologists, radiologists and (molecular) pathologists.
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http://dx.doi.org/10.1111/liv.14547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383747PMC
July 2020

Genetics of Hepatocellular Carcinoma: Approaches to Explore Molecular Diversity.

Hepatology 2021 Jan 8;73 Suppl 1:14-26. Epub 2020 Dec 8.

Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Université Paris 13, Functional Genomics of Solid Tumors Laboratory, Paris, France.

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http://dx.doi.org/10.1002/hep.31394DOI Listing
January 2021

Corrigendum to: "BAP1 mutations define a homogeneous subgroup of hepatocellular carcinoma with fibrolamellar-like features and activated PKA" [J Hepatol (2020) 1-13].

J Hepatol 2020 Jul 29;73(1):225-226. Epub 2020 Apr 29.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; Functional Genomics of Solid Tumors laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France; Hôpital Européen Georges Pompidou, APHP, F-75015 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.04.004DOI Listing
July 2020

Long-term Evolution of Hepatocellular Adenomas at MRI Follow-up.

Radiology 2020 05 17;295(2):361-372. Epub 2020 Mar 17.

From the University of Paris, Paris, France (F.V., M.R., F.C., O.S., D.V., V.P., V.V.); Departments of Radiology (M.R., M.D.B., V.V.), Liver Transplantation and Hepatobiliary Surgery (F.C., S.D., O.S.), and Hepatology (D.V.), and Pathology Department (V.P.), University Hospitals Paris Nord Val de Seine, Beaujon, Clichy, Hauts-de-Seine, France; INSERM, UMR 1149, Paris, France (M.R., F.C., O.S., D.V., M.D.B., V.P., V.V.); Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC (K.R.C.); INSERM, UMR 1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France (J.Z.), Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy (F.V.).

Background Hepatocellular adenomas (HCAs) are rare benign liver tumors. Guidelines recommend continued surveillance of patients diagnosed with HCAs, but these guidelines are mainly based on small studies or expert opinion. Purpose To analyze the long-term evolution of HCAs, including solitary and multiple lesions, and to identify predictive features of progression with MRI. Materials and Methods In a retrospective study, patients diagnosed with pathologically proven solitary or multiple HCAs between January 2004 and December 2015 were included; β-catenin-mutated HCAs and HCAs with foci of malignancy were considered to be at risk for progression. MRI examinations were analyzed, and tumor evolution was evaluated by using Response Evaluation Criteria in Solid Tumors, version 1.1. Student Mann-Whitney, χ, Fisher exact, and McNemar tests were used, as appropriate. Results In total, 118 patients (mean age, 40 years ± 10 [standard deviation]; 108 women) were evaluated, including 41 with a solitary HCA (mean age, 40 years ± 14; 36 women) and 77 with multiple HCAs (mean age, 40 years ± 10; 72 women). At a median follow-up of 5 years, 37 of 41 (90%) patients with a solitary HCA and 55 of 77 (71%) patients with multiple HCAs showed stable or regressive disease. After resection of solitary HCAs, new lesions appeared in only two of 29 (7%) patients, both of whom had HCAs at risk of progression. In patients with multiple HCAs, hepatocyte nuclear factor 1α-inactivated HCAs showed a higher rate of progression compared with inflammatory HCAs (11 of 26 [42%] vs seven of 37 [19%], = .04) despite lower use (28 of 32 patients [88%] vs 45 of 45 patients [100%]; = .03) and shorter duration (mean, 12.0 years ± 7.5 vs 19.2 years ± 9.2; = .001) of oral contraceptive intake. Conclusion Long-term MRI follow-up showed that 78% of hepatocellular adenomas had long-term stability or regression. After resection of solitary hepatocellular adenomas, new lesions occurred only in hepatocellular adenomas at risk of progression. Patients with multiple hepatocellular adenomas were more likely to show progressive disease, with hepatic nuclear factor 1α-inactivated hepatocellular adenomas being the most common subtype showing progression. © RSNA, 2020
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http://dx.doi.org/10.1148/radiol.2020191790DOI Listing
May 2020

Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival.

Mol Oncol 2020 06 10;14(6):1207-1223. Epub 2020 Mar 10.

Centre de Recherche des Cordeliers, Inserm, Sorbonne Université, Université de Paris, Functional Genomics of Solid Tumors laboratory, France.

Development of precision medicine for malignant pleural mesothelioma (MPM) requires a deep knowledge of tumor heterogeneity. Histologic and molecular classifications and histo-molecular gradients have been proposed to describe heterogeneity, but a deeper understanding of gene mutations in the context of MPM heterogeneity is required and the associations between mutations and clinical data need to be refined. We characterized genetic alterations on one of the largest MPM series (266 tumor samples), well annotated with histologic, molecular and clinical data of patients. Targeted next-generation sequencing was performed focusing on the major MPM mutated genes and the TERT promoter. Molecular heterogeneity was characterized using predictors allowing classification of each tumor into the previously described molecular subtypes and the determination of the proportion of epithelioid-like and sarcomatoid-like components (E/S.scores). The mutation frequencies are consistent with literature data, but this study emphasized that TERT promoter, not considered by previous large sequencing studies, was the third locus most affected by mutations in MPM. Mutations in TERT promoter, NF2, and LATS2 were more frequent in nonepithelioid MPM and positively associated with the S.score. BAP1, NF2, TERT promoter, TP53, and SETD2 mutations were enriched in some molecular subtypes. NF2 mutation rate was higher in asbestos unexposed patient. TERT promoter, NF2, and TP53 mutations were associated with a poorer overall survival. Our findings lead to a better characterization of MPM heterogeneity by identifying new significant associations between mutational status and histologic and molecular heterogeneity. Strikingly, we highlight the strong association between new mutations and overall survival.
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http://dx.doi.org/10.1002/1878-0261.12651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266286PMC
June 2020

JHEP Reports: A new EASL open access journal.

JHEP Rep 2019 May 25;1(1). Epub 2019 Mar 25.

Centre de recherche des Cordeliers, Inserm U1138, Université Paris Descartes, Sorbonne Université, Université Paris Diderot, 15 rue de l'école de médecine, 75006 Paris, France.

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http://dx.doi.org/10.1016/j.jhepr.2019.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001529PMC
May 2019

Recurrent chromosomal rearrangements of , and activating JAK/STAT pathway in inflammatory hepatocellular adenomas.

Gut 2020 09 6;69(9):1667-1676. Epub 2020 Jan 6.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm,Université de Paris, Université Paris 13, Functional Genomics of Solid Tumors laboratory, F-75006 Paris, France

Background: 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.

Methods: 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.

Results: We identified 296 IHCA (45%), 81% of them were mutated in either (61%), (8%), (5%), (3%) or (2%). Among non-mutated IHCA, RNA sequencing identified recurrent chromosome rearrangement involving or genes. fusions were identified in 8 IHCA, involving C-terminal part of genes highly expressed in the liver (, , ) fused with exon 33-35 to 43 of including the tyrosine kinase domain. In two cases a truncated transcript from exon 36 to 43 was identified. rearrangements were validated by fluorescence in situ hybridisation (FISH) and led to overexpression. Among the 5 IHCA with rearrangements, 5 different partners were identified (, , , ) fused to a common region in that included exon 3-8. No overexpression of transcript was detected but the predicted chimeric proteins lacked the auto-inhibitory SH2-SH3 domains. In two IHCA, we identified truncated 3'UTR of associated with overexpression of the transcript.

Conclusion: Recurrent chromosomal alterations involving , or genes lead to activation of the JAK/STAT pathway in IHCAs.
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http://dx.doi.org/10.1136/gutjnl-2019-319790DOI Listing
September 2020

BAP1 mutations define a homogeneous subgroup of hepatocellular carcinoma with fibrolamellar-like features and activated PKA.

J Hepatol 2020 05 18;72(5):924-936. Epub 2019 Dec 18.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; Functional Genomics of Solid Tumors laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France; Hôpital Européen Georges Pompidou, APHP, F-75015 Paris, France. Electronic address:

Background & Aims: DNAJB1-PRKACA fusion is a specific driver event in fibrolamellar carcinoma (FLC), a rare subtype of hepatocellular carcinoma (HCC) that occurs in adolescents and young adults. In older patients, molecular determinants of HCC with mixed histological features of HCC and FLC (mixed-FLC/HCC) remain to be discovered.

Methods: A series of 151 liver tumors including 126 HCC, 15 FLC, and 10 mixed-FLC/HCC were analyzed by RNAseq and whole-genome- or whole-exome sequencing. Western blots were performed to validate genomic discoveries. Results were validated using the TCGA database.

Results: Most of the mixed-FLC/HCC RNAseq clustered in a robust subgroup of 17 tumors, which all had mutations or translocations inactivating BAP1, the gene encoding BRCA1-associated protein-1. Like FLC, BAP1-HCC were significantly enriched in females, patients with a lack of chronic liver disease, and fibrotic tumors compared to non-BAP1 HCC. However, patients were older and had a poorer prognosis than those with FLC. BAP1 tumors were immune hot, showed progenitor features and did not show DNAJB1-PRKACA fusion, while almost none of these tumors had mutations in CTNNB1, TP53 and TERT promoter. In contrast, 80% of the BAP1 tumors showed a chromosome gain of PRKACA at 19p13, combined with a loss of PRKAR2A (coding for the inhibitory regulatory subunit of PKA) at 3p21, leading to a high PRKACA/PRKAR2A ratio at the mRNA and protein levels.

Conclusion: We have characterized a subgroup of BAP1-driven HCC with fibrolamellar-like features and a dysregulation of the PKA pathway, which could be at the root of the clinical and histological similarities between BAP1 tumors and DNAJB1-PRKACA FLCs.

Lay Summary: Herein, we have defined a homogeneous subgroup of hepatocellular carcinomas in which the BAP1 gene is inactivated. This leads to the development of cancers with features similar to those of fibrolamellar carcinoma. These tumors more frequently develop in females without chronic liver disease or cirrhosis. The presence of PKA activation and T cell infiltrates suggest that these tumors could be treated with PKA inhibitors or immunomodulators.
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http://dx.doi.org/10.1016/j.jhep.2019.12.006DOI Listing
May 2020

Journal of Hepatology: The Home of Liver Research, 2015-2019.

J Hepatol 2019 12;71(6):1065-1069

Journal of Hepatology, European Association from the Study of the Liver, Geneva, Switzerland.

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http://dx.doi.org/10.1016/j.jhep.2019.09.017DOI Listing
December 2019

Natural history of liver adenomatosis: A long-term observational study.

J Hepatol 2019 12 13;71(6):1184-1192. Epub 2019 Aug 13.

Department of Hepatology and Gastroenterology, University Hospital of Tours, Tours, France.

Background & Aims: Liver adenomatosis (LA) is characterized by the presence of at least 10 hepatocellular adenomas (HCAs), but the natural history of this rare liver disorder remains unclear. Thus, we aimed to reappraise the natural history and the risk of complications in a cohort of patients with at least 10 HCAs.

Methods: We analyzed the natural history of 40 patients with LA, excluding glycogen storage disorders, in a monocentric cohort. Pathological examination was performed, with immunostaining and molecular biology carried out on surgical specimens or liver biopsies.

Results: Forty patients (36 female) were included with a median follow-up of 10.6 (1.9-26.1) years. Six (15%) patients had familial LA, all with germline HNF1A mutations. Median age at diagnosis was 39 (9-55) years. Thirty-three (94%) women had a history of oral contraception, and 29 (81%) women had a pregnancy before LA diagnosis. Overall, thirty-seven (93%) patients underwent surgery at diagnosis. Classification of HCAs showed 46% of patients with HNF1A-mutated HCA, 31% with inflammatory HCA, 3% with sonic hedgehog HCA, 8% with unclassified HCA. Only 15% of the patients demonstrated a "mixed LA" with different HCA subtypes. Hepatic complications were identified in 7 patients: 1 patient (3%) died from recurrent hepatocellular carcinoma after liver transplantation; 6 (15%) had hemorrhages, of which 5 occurred at diagnosis, with 1 fatal case during pregnancy, and 2 occurred in male patients with familial LA. Four patients (10%) had repeated liver resections. Finally, 4 (10%) patients developed extrahepatic malignancies during follow-up.

Conclusions: The diversity in HCA subtypes, as well as the occurrence of bleeding and malignant transformation during long-term follow-up, underline the heterogeneous nature of LA, justifying close and specific management. In patients with germline HNF1A mutation, familial LA occurred equally frequently in males and females, with a higher rate of bleeding in male patients.

Lay Summary: Liver adenomatosis is a rare disease characterized by the presence of 10 or more hepatocellular adenomas that may rarely be of genetic origin. Patients with liver adenomatosis have multiple adenomas of different subtypes, with a risk of bleeding and malignant transformation that justify a specific management and follow-up.
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http://dx.doi.org/10.1016/j.jhep.2019.08.004DOI Listing
December 2019

Immunogenomics of Metastatic Clear-Cell Renal Cell Carcinoma: Remarkable Response to Nivolumab in a Patient With a Pathogenic Germ Line BRCA1 Mutation.

Clin Genitourin Cancer 2019 10 11;17(5):e909-e912. Epub 2019 Jul 11.

Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium. Electronic address:

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http://dx.doi.org/10.1016/j.clgc.2019.06.013DOI Listing
October 2019

Adeno-associated virus in the liver: natural history and consequences in tumour development.

Gut 2020 04 2;69(4):737-747. Epub 2019 Aug 2.

Centre de Recherche des Cordeliers, Sorbonne Universités, INSERM, Paris, Île-de-France, France.

Objective: Adeno-associated virus (AAV) is a defective mono-stranded DNA virus, endemic in human population (35%-80%). Recurrent clonal AAV2 insertions are associated with the pathogenesis of rare human hepatocellular carcinoma (HCC) developed on normal liver. This study aimed to characterise the natural history of AAV infection in the liver and its consequence in tumour development.

Design: Viral DNA was quantified in tumour and non-tumour liver tissues of 1461 patients. Presence of episomal form and viral mRNA expression were analysed using a DNAse/TaqMan-based assay and quantitative RT-PCR. In silico analyses using viral capture data explored viral variants and new clonal insertions.

Results: AAV DNA was detected in 21% of the patients, including 8% of the tumour tissues, equally distributed in two major viral subtypes: one similar to AAV2, the other hybrid between AAV2 and AAV13 sequences. Episomal viral forms were found in 4% of the non-tumour tissues, frequently associated with viral RNA expression and human herpesvirus type 6, the candidate natural AAV helper virus. In 30 HCC, clonal AAV insertions were recurrently identified in , , , , and /. AAV insertion triggered oncogenic overexpression through multiple mechanisms that differ according to the localisation of the integration site.

Conclusion: We provided an integrated analysis of the wild-type AAV infection in the liver with the identification of viral genotypes, molecular forms, helper virus relationship and viral integrations. Clonal AAV insertions were positive selected during HCC development on non-cirrhotic liver challenging the notion of AAV as a non-pathogenic virus.
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http://dx.doi.org/10.1136/gutjnl-2019-318281DOI Listing
April 2020
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