In the Genomics of Pediatric Liver Tumors group, we analyze different genomic datasets (whole-exome and whole-genome sequencing, RNA-seq, DNA methylation data), and we develop innovative computational tools to better understand the origin and the molecular diversity of tumors. We explore several research axes, as described below.
Identification of genes driving hepatocellular carcinogenesis
Tumor cells harbor numerous molecular alterations (mutations, chromosome gains and losses, translocations) that can alter the function or the activity of target genes. We develop computational approaches to integrate these alterations and identify genes recurrently altered, which are likely to play a key role in oncogenesis. By analyzing the exome sequences of 250 hepatocellular carcinomas, we recently identified 161 putative driver genes belonging to 11 major cellular pathways (Schulze, Imbeaud, Letouzé et al., Nat Genet 2015). We now analyze whole-genome sequencing data to identify non-coding mutations likely to affect the regulatory sequences of target genes, like the activating mutations of TERT promoter (Nault et al., Nat Commun 2013).
Mutational signatures
Somatic mutations that drive cancer progression are the consequence of spontaneous enzymatic conversions, replication errors, or mutagenic exposures like tobacco or UV light. These mutational processes leave imprints on the tumor genome that can be identified as mutational signatures, caracterized by specific types of mutations or mutations occurring in specific genomic contexts. For instance, tobacco carcinogenes induce mostly C>A mutations, whereas defects in DNA mismatch repair genes lead to an enriched frequency of C>T mutations in NCG trinucleotide context. By analyzing a large series of liver tumors by whole-exome sequencing, we have identified 2 new mutational signatures caracteristic of liver tumors (Schulze, Imbeaud, Letouzé et al., Nat Genet 2015). One of these signatures, caracterized by frequent C>A mutations at GCC trinucleotides, could be related to exposure to aflatoxin B1, a toxin produced by a mushroom in warm and wet countries of Africa and Asia. We now analyze whole-genome sequencing data from a new series of tumors, associated with diverse risk factors, to identify new signatures and distinguish mutational process operative in the early and late steps of oncogenesis. In collaboration with Pr Pierre Laurent-Puig’s team (UMR-S 1147), we also analyze the mutational signatures of other tumor types, like lung and colorectal cancer.
Clonal evolution of liver tumors
Tumors develop through the expansion of cell clones having acquired genomic alterations that confer them a proliferative advantage over surrounding cells. Several clones may coexist within a single tumor, including a dominant clone and one or more minor subclones. Understanding tumor heterogeneity is essential as subclones may harbor specific genetic defects conferring resistance to treatment. Besides, reconstructing the clonal architecture of a tumor allows to distinguish early from late genetic alterations, and to better understand the role of each driver gene. We currently analyze whole-genome sequencing data to reconstruct the clonal architecture of 50 liver tumors. In particular, we analyze cases of adenomas having progressed to carcinomas (Pilati et al., Cancer Cell 2014), to identify the molecular events triggering malignant transformation.
Epigenetic signatures of oncogenic processes
Epigenetic profiles (DNA methylation, histone modifications, chromatin conformation) are highly rearranged in tumor cells. Besides, numerous epigenetic regulators, implicated in DNA (de)methylation or chromatin remodeling, are frequently mutated, in particular in liver cancers. However, the mechanistic link between these molecular alterations and the epigenetic profiles of tumors remains poorly understood. By analyzing the methylome of a large series of liver tumors previously characterized by whole-exome sequencing, we wish to identify specific DNA methylation signatures. We will then correlate these signatures with clinical (exposure to risk factors) and molecular annotations (mutations in epigenetic regulators) to identify the cause of each pattern. This project aims at understanding how altered epigenetic profiles are established, and how the affect the transcriptome of tumor cells. In collaboration with INSERM UMR970 team (Dr Judith Favier), we also study the hypermethylator phenotype induced by succinate dehydrogenase mutations in paraganglioma (Letouzé et al., Cancer Cell 2013).
Insertional mutagenesis by AAV and HBV virus
Virus, including hepatitis B virus (HBV) and hepatitis C, are major causes of hepatocellular carcinomas (HCC) worldwide. HBV is a well-known oncogenic DNA virus in liver tumors that induces insertional mutagenesis, chromosome instability and expression of oncogenic viral proteins. Currently only 2 other DNA viruses (merkel polyomavirus and human papilloma virus) are known to induce oncogenic insertional mutagenesis in human. Recently we obtained very innovative results showing that genomic approaches can help to identify new risk factors of HCC and modified our understanding of the disease. We showed that the adeno-associated virus type 2 (AAV2) is involved in HCC development on normal liver due to insertional mutagenesis in cancer genes (1). Currently, AAV is the 8th virus known associated to human cancer. The first identification of recurrent oncogenic AAV2 insertions in liver tumors leads us to develop a research project aiming to identify viral sequences and possibly new AAV integration sites in different types of liver tumors. As recombinant AAV is used as a vector for gene therapy in human clinical trials, a fine understanding of the mechanisms of carcinogenesis of the wild type virus is mandatory to assess the potential risk of cancer development after gene therapy. The objective is to quantify the contribution of AAV infection to the development of liver tumors in patients with liver disease related to various etiologies or without liver disease. We aim to identify new risk factors of hepatocellular carcinoma by analyzing tumor genomes and to validate them in epidemio-molecular studies through a comprehensive analysis of the tumor, host and viral genomes.
Transcriptome deregulation in liver tumors
Transcriptome profiling of liver tumors using DNA microarrays allowed us to identify homogeneous molecular groups of tumors, associated with distinct molecular alterations and risk factors (Boyault et al., Hepatology 2007). With the advent of high-throughput sequencing, we can now study the transcriptome by directly sequencing the RNAs extracted from a tumor sample (RNA-seq technique). These data give access to an unprecedented wealth of information. In addition to gene expression levels, RNA-seq data give access to the structure and sequence of transcripts, and allow the discovery of new genes. We have generated in the lab the RNA-seq profiles of a large series of liver tumors. We now develop innovative bioinformatic approaches to (1) refine the molecular classfication of liver tumors, (2) analyze the deregulation of non-coding RNAs, (3) detect alternative splicing and allele specific expression in tumors, and (4) identify the mutations that are actually expressed (more likely to play an oncogenic role) and RNA editing events.
Development of an annotation database
The development of genetics and new in-depth and high throughput technologies results in massive data production. Moreover, the multiplicity of programs and genomic annotations through “genome browsers” has created a “jungle” of terminology which requires the establishment and use of a unified vocabulary. In this context, we design and develop a database for structuring, annotation and exploitation of this mass of data generated by genomics programs. This project will, in collaboration with the EBCI Company, the implementation of an efficient IT infrastructure to meet our mixed data model, including clinic, histological and molecular datasets, to lead (1) the optimization of the architecture of our data model, (2) the management of the annotation including updates, and (3) optimizing a Web server to allow biologists to efficiently query data.
APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures. Morcrette G, Hirsch TZ, Badour E, Pilet J, Caruso S, Calderaro J, Martin Y, Imbeaud S, Letouzé E, Rebouissou S, Branchereau S, Taque S, Chardot C, Guettier C, Scoazec JY, Fabre M, Brugières L, Zucman-Rossi J. Oncoimmunology. 2019 Mar 28;8(6):e1583547. doi: 10.1080/2162402X.2019.1583547. eCollection 2019.
Analysis of Liver Cancer Cell Lines Identifies Agents With Likely Efficacy Against Hepatocellular Carcinoma and Markers of Response. Caruso S, Calatayud AL, Pilet J, La Bella T, Rekik S, Imbeaud S, Letouzé E, Meunier L, Bayard Q, Rohr-Udilova N, Péneau C, Grasl-Kraupp B, de Koning L, Ouine B, Bioulac-Sage P, Couchy G, Calderaro J, Nault JC, Zucman-Rossi J, Rebouissou S. Gastroenterology. 2019 May 4. pii: S0016-5085(19)36771-X. doi: 10.1053/j.gastro.2019.05.001.
A 17-Beta-Hydroxysteroid Dehydrogenase 13 Variant Protects From Hepatocellular Carcinoma Development in Alcoholic Liver Disease. Yang J, Trépo E, Nahon P, Cao Q, Moreno C, Letouzé E, Imbeaud S, Bayard Q, Gustot T, Deviere J, Bioulac-Sage P, Calderaro J, Ganne-Carrié N, Laurent A, Blanc JF, Guyot E, Sutton A, Ziol M, Zucman-Rossi J, Nault JC. Hepatology. 2019 Mar 25. doi: 10.1002/hep.30623.
Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress. Bayard Q, Meunier L, Peneau C, Renault V, Shinde J, Nault JC, Mami I, Couchy G, Amaddeo G, Tubacher E, Bacq D, Meyer V, La Bella T, Debaillon-Vesque A, Bioulac-Sage P, Seror O, Blanc JF, Calderaro J, Deleuze JF, Imbeaud S, Zucman-Rossi J, Letouzé E. Nat Commun. 2018 Dec 7;9(1):5235. doi: 10.1038/s41467-018-07552-9.
PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases. Yang J, Trépo E, Nahon P, Cao Q, Moreno C, Letouzé E, Imbeaud S, Gustot T, Deviere J, Debette S, Amouyel P, Bioulac-Sage P, Calderaro J, Ganne-Carrié N, Laurent A, Blanc JF, Guyot E, Sutton A, Ziol M, Zucman-Rossi J, Nault JC. Int J Cancer. 2019 Feb 1;144(3):533-544. doi: 10.1002/ijc.31910. Epub 2018 Nov 9.
Systemic AA Amyloidosis Caused by Inflammatory Hepatocellular Adenoma. Calderaro J, Letouzé E, Bayard Q, Boulai A, Renault V, Deleuze JF, Bestard O, Franco D, Zafrani ES, Nault JC, Moutschen M, Zucman-Rossi J. N Engl J Med. 2018 Sep 20;379(12):1178-1180. doi: 10.1056/NEJMc1805673.
Palimpsest: an R package for studying mutational and structural variant signatures along clonal evolution in cancer. Shinde J, Bayard Q, Imbeaud S, Hirsch TZ, Liu F, Renault V, Zucman-Rossi J, Letouzé E. Bioinformatics. 2018 Oct 1;34(19):3380-3381. doi: 10.1093/bioinformatics/bty388.
Argininosuccinate synthase 1 and periportal gene expression in sonic hedgehog hepatocellular adenomas. Nault JC, Couchy G, Caruso S, Meunier L, Caruana L, Letouzé E, Rebouissou S, Paradis V, Calderaro J, Zucman-Rossi J. Hepatology. 2018 Sep;68(3):964-976. doi: 10.1002/hep.29884. Epub 2018 Jun 6.
Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis. Letouzé E, Shinde J, Renault V, Couchy G, Blanc JF, Tubacher E, Bayard Q, Bacq D, Meyer V, Semhoun J, Bioulac-Sage P, Prévôt S, Azoulay D, Paradis V, Imbeaud S, Deleuze JF, Zucman-Rossi J.
PhD
MD, PhD
“Therapeutic Targets in liver tumors”, led by Sandra Rebouissou Ph.D. & Jean-Charles NAULT M.D Ph.D., develops an integrated approach that extends from the study of the molecular basis of tumor initiation and progression to applications of targeted treatment and the identification of biomarkers predicting the therapeutic response. For this purpose, they develop two main research axes:
1) translational studies based on screening of anti-tumor molecules on large collections of adult and pediatric human liver cancer cell lines characterized extensively at the molecular level, combined with genomic analysis of tumor samples from patients included in clinical trials in order to link tumor molecular alterations and microenvironment to the clinical therapeutic response.
2) basic studies aimed at modeling in cellulo and in vivo the genetic alterations identified in human tumors in order to better identify the driver genes and their role in liver oncogenesis, and to understand the mechanisms of oncogenic cooperations.
MD, PhD
PhD
MD
MD
PhD
MD, PhD
PharmD
APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures. Morcrette G, Hirsch TZ, Badour E, Pilet J, Caruso S, Calderaro J, Martin Y, Imbeaud S, Letouzé E, Rebouissou S, Branchereau S, Taque S, Chardot C, Guettier C, Scoazec JY, Fabre M, Brugières L, Zucman-Rossi J. Oncoimmunology. 2019 Mar 28;8(6):e1583547. doi: 10.1080/2162402X.2019.1583547.
Analysis of Liver Cancer Cell Lines Identifies Agents With Likely Efficacy Against Hepatocellular Carcinoma and Markers of Response. Caruso S, Calatayud AL, Pilet J, La Bella T, Rekik S, Imbeaud S, Letouzé E, Meunier L, Bayard Q, Rohr-Udilova N, Péneau C, Grasl-Kraupp B, de Koning L, Ouine B, Bioulac-Sage P, Couchy G, Calderaro J, Nault JC, Zucman-Rossi J, Rebouissou S. Gastroenterology. 2019 May 4. pii: S0016-5085(19)36771-X. doi: 10.1053/j.gastro.2019.05.001.
Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations. Adebayo Michael AO, Ko S, Tao J, Moghe A, Yang H, Xu M, Russell JO, Pradhan-Sundd T, Liu S, Singh S, Poddar M, Monga JS, Liu P, Oertel M, Ranganathan S, Singhi A, Rebouissou S, Zucman-Rossi J, Ribback S, Calvisi D, Qvartskhava N, Görg B, Häussinger D, Chen X, Monga SP. Cell Metab. 2019 May 7;29(5):1135-1150.e6. doi: 10.1016/j.cmet.2019.01.002. Epub 2019 Jan 31.
Argininosuccinate synthase 1 and periportal gene expression in sonic hedgehog hepatocellular adenomas. Nault JC, Couchy G, Caruso S, Meunier L, Caruana L, Letouzé E, Rebouissou S, Paradis V, Calderaro J, Zucman-Rossi J. Hepatology. 2018 Sep;68(3):964-976. doi: 10.1002/hep.29884. Epub 2018 Jun 6.
Note of caution: Contaminations of hepatocellular cell lines. Rebouissou S, Zucman-Rossi J, Moreau R, Qiu Z, Hui L. J Hepatol. 2017 Nov;67(5):896-897. doi: 10.1016/j.jhep.2017.08.002. Epub 2017 Aug 12.
1: APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures. Morcrette G, Hirsch TZ, Badour E, Pilet J, Caruso S, Calderaro J, Martin Y, Imbeaud S, Letouzé E, Rebouissou S, Branchereau S, Taque S, Chardot C, Guettier C, Scoazec JY, Fabre M, Brugières L, Zucman-Rossi J. Oncoimmunology. 2019 Mar 28;8(6):e1583547. doi: 10.1080/2162402X.2019.1583547. eCollection 2019. PMID: 31069152
Caruso S, Calatayud AL, Pilet J, La Bella T, Rekik S, Imbeaud S, Letouzé E, Meunier L, Bayard Q, Rohr-Udilova N, Péneau C, Grasl-Kraupp B, de Koning L, Ouine B, Bioulac-Sage P, Couchy G, Calderaro J, Nault JC, Zucman-Rossi J, Rebouissou S. Gastroenterology. 2019 May 4. pii: S0016-5085(19)36771-X. doi: 10.1053/j.gastro.2019.05.001. [Epub ahead of print] PMID:31063779
3: Polyploidy spectrum: a new marker in HCC classification. Bou-Nader M, Caruso S, Donne R, Celton-Morizur S, Calderaro J, Gentric G, Cadoux M, L’Hermitte A, Klein C, Guilbert T, Albuquerque M, Couchy G, Paradis V, Couty JP, Zucman-Rossi J, Desdouets C. Gut. 2019 Apr 12. pii: gutjnl-2018-318021. doi: 10.1136/gutjnl-2018-318021. [Epub ahead of print] PMID:30979717
4: Dynamics and predicted drug response of a gene network linking dedifferentiation with beta-catenin dysfunction in hepatocellular carcinoma. Gérard C, Di-Luoffo M, Gonay L, Caruso S, Couchy G, Loriot A, Castven D, Tao J, Konobrocka K, Cordi S, Monga SP, Hanert E, Marquardt JU, Zucman-Rossi J, Lemaigre FP. J Hepatol. 2019 Apr 3. pii: S0168-8278(19)30195-3. doi: 10.1016/j.jhep.2019.03.024. [Epub ahead of print] PMID:30953666
5: A 17-Beta-Hydroxysteroid Dehydrogenase 13 Variant Protects From Hepatocellular Carcinoma Development in Alcoholic Liver Disease. Yang J, Trépo E, Nahon P, Cao Q, Moreno C, Letouzé E, Imbeaud S, Bayard Q, Gustot T, Deviere J, Bioulac-Sage P, Calderaro J, Ganne-Carrié N, Laurent A, Blanc JF, Guyot E, Sutton A, Ziol M, Zucman-Rossi J, Nault JC. Hepatology. 2019 Mar 25. doi: 10.1002/hep.30623. [Epub ahead of print] PMID:30908678
6: Dissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications. Blum Y, Meiller C, Quetel L, Elarouci N, Ayadi M, Tashtanbaeva D, Armenoult L, Montagne F, Tranchant R, Renier A, de Koning L, Copin MC, Hofman P, Hofman V, Porte H, Le Pimpec-Barthes F, Zucman-Rossi J, Jaurand MC, de Reyniès A, Jean D. Nat Commun. 2019 Mar 22;10(1):1333. doi: 10.1038/s41467-019-09307-6. PMID:30902996
7: Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations. Adebayo Michael AO, Ko S, Tao J, Moghe A, Yang H, Xu M, Russell JO, Pradhan-Sundd T, Liu S, Singh S, Poddar M, Monga JS, Liu P, Oertel M, Ranganathan S, Singhi A, Rebouissou S, Zucman-Rossi J, Ribback S, Calvisi D, Qvartskhava N, Görg B, Häussinger D, Chen X, Monga SP. Cell Metab. 2019 May 7;29(5):1135-1150.e6. doi: 10.1016/j.cmet.2019.01.002. Epub 2019 Jan 31. PMID:30713111
8: Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress. Bayard Q, Meunier L, Peneau C, Renault V, Shinde J, Nault JC, Mami I, Couchy G, Amaddeo G, Tubacher E, Bacq D, Meyer V, La Bella T, Debaillon-Vesque A, Bioulac-Sage P, Seror O, Blanc JF, Calderaro J, Deleuze JF, Imbeaud S, Zucman-Rossi J, Letouzé E. Nat Commun. 2018 Dec 7;9(1):5235. doi: 10.1038/s41467-018-07552-9. PMID:30531861
9: Fibroblast Growth Factor Receptor-2 Polymorphism rs2981582 is Correlated With Progression-free Survival and Overall Survival in Patients With Metastatic Clear-cell Renal Cell Carcinoma Treated With Sunitinib. Vanmechelen M, Lambrechts D, Van Brussel T, Verbiest A, Couchy G, Schöffski P, Dumez H, Debruyne PR, Lerut E, Machiels JP, Richard V, Albersen M, Verschaeve V, Oudard S, Méjean A, Wolter P, Zucman-Rossi J, Beuselinck B. Clin Genitourin Cancer. 2019 Apr;17(2):e235-e246. doi: 10.1016/j.clgc.2018.11.002. Epub 2018 Nov 16. PMID:30527746
10: Assessment of signaling pathway inhibitors and identification of predictive biomarkers in malignant pleural mesothelioma. Tranchant R, Quetel L, Montagne F, De Wolf J, Meiller C, De Koning L, Le Pimpec-Barthes F, Zucman-Rossi J, Jaurand MC, Jean D. Lung Cancer. 2018 Dec;126:15-24. doi: 10.1016/j.lungcan.2018.10.015. Epub 2018 Oct 16. PMID:30527180
Collaborators: S Imbeaud (IR), C Peneau (PhD st), T La Bella (PhD st), J Zucman-Rossi (PUPH);
Involvement of pathogen agents in human carcinogenesis remain to be investigated. Our recent identification of AAV2 as the fourth virus involved in insertional mutagenesis prompt us to develop a project to evaluate consequences of HBV, HCV and AAV infections in liver tumorigenesis by integrating the analysis of viral and tumor genome alterations. Our aim is to reconstruct the natural history of the viruses (genome variation, replication, structural alterations, selection…) in the context of tumor cell selection in patients putatively treated by antiviral therapies or exposed to multiple pathogens. We will also search for additional pathogens in WGS data and collaborate with the international ICGC viruses project.
Fundings: LNCC, ANRS, Biomerieux Foundation
Collaborators: G Morcrette (PhD st), E Letouzé (CR Inserm), J Pilet (PhD st), S Imbeaud (IR), G Couchy (IE, PhD st), Julien Calderaro (pathologist), JC Nault (MCUPH), J Zucman-Rossi (PUPH); in cooperation with SIOPEL,
Most of pediatric liver neoplasms are poorly analyszed at the genomic and molecular level. They include hepatocellular carcinomas (HCC), fibrolamellar carcinomas (FLC), hepatoblastomas (HB), transitional liver cell tumors (TLCT) and also benign neoplasms, hepatocellular adenomas (HCA) and focal nodular hyperplasias (FNH). We aim to perform an integrated genomic analysis of these pediatric hepatocellular tumors to better understand their mechanism of tumorigenesis. To this purpose, we have collected a series of 193 patients with pediatric frozen liver tumors part of the national HEPATOBIO tumor resource. Within this series, 48 cases/67 frozen tumor samples have been selected for whole genome sequencing (WGS) and RNA sequencing (RNAseq) within the GEPELIN project funded by France Génomique for the WGS part. Our specific aims are to (1) identify putative driver genes altered in pediatric tumors and validate them functionally (2) perform new transcriptomic classification to derive new altered pathways and diagnostic/prognostic markers, (3) characterize the mutational and chromosome rearrangement signatures to identify new mechanism of carcinogenesis (4) search for therapeutic targets. These results will be compared with the adult liver tumors data that we have accumulated in the lab.
Fundings: LNCC, France Genomique.
Collaborators: E Letouzé , J Shinde , S Imbeaud (IR), L Meunier (PhD st), Q Bayard (M2), T Hirsch (Post-doc), J Zucman-Rossi (PUPH
In the last 5 years, we have generated large genomic data sets including 350 tumors analyzed by whole exome sequencing, 270 by RNA-seq, 250 by methylation arrays and 100 by whole genome sequencing. We will use this exceptional resource to unravel key questions in the natural history of liver cancers. (1) What mutational processes drive tumorigenesis? We have so far identified 10 point-mutation signatures associated with known (aflatoxin B1, tobacco) or unknown mutagenic processes in liver cancers. We will extend these analyses to signatures of indels and structural rearrangements, and perform a meta-analysis of all published liver cancer data sets to unravel the association of signatures with risk factors and predisposing variants. (2) What are the missing drivers in liver cancers? Analysis of coding mutations by us and others revealed tens of driver genes and pathways but 30% of tumors still have no identified driver event. In order to identify non-coding driver alterations, we will use whole genome and RNA-seq data to systematicallly screen for mutations and structural rearrangements modifying regulatory regions, chromatin context and 3’ UTR sequences and affecting mRNA expression and stability. (3) How to the genomic, epigenomic and transcriptional layers interact in tumor cells? We will develop innovative strategies to unravel the connexions between genomic alterations, DNA methylation and gene expression profiles. (4) What is the timing of genomic alterations along tumorigenesis? We and others have developed statistical approaches to time mutational signatures, copy-number alterations and driver events in the life history of a cancer using intra-tumor heterogeneity. We will conduct an ambitious project to analyze the evolution of genomic, transcriptional and micro-environment features in 25 patients with multiple samples along the treatment.
Fundings: Cancer environment, HTE HETCOLI, France Genomique, Canceropole
E Letouzé (CR Inserm), P Nahon (PUPH), E Trepo (Post-doc), J Yang (Ph st), JC Nault (MCUPH), Zucman-Rossi (PUPH)
Candidate gene studies have uncovered a limited number of variants reproducibly linked to hepatocellular carcinoma (HCC). The HECAM project aims to identify newgermline variants predisposing to HCC in the French population and to test their ability to modify patient care in clinical practice. Therefore, a genome-wide association study will be performed in a multicenter cohort of chronic liver disease patients with (n = 2,066) and without (n = 2,666) HCC using the Illumina Infinium Global Screening Array including ~ 660,000 markers). Validation of the top variants will be performed in two French replication cohorts of cirrhotic patients included in HCC surveillance programs (n = 2,249). The performance for HCC risk stratification will be finally assessed through integration of genetic information into specific algorithm-based prediction models. An original integrative approach including somatic information already generated will be used for prioritizing variants impacting liver carcinogenesis. Finally, genotype-phenotype associations will be performed to build prognostic models. We also plan to analyze benign liver tumors to search for genetic predisposition to the development of hepatocellular adenoma in a cohort of 500 patients with in parallel an epidemiological study.
Fundings: HECAM, ANRS, AFEF
APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures. Morcrette G, Hirsch TZ, Badour E, Pilet J, Caruso S, Calderaro J, Martin Y, Imbeaud S, Letouzé E, Rebouissou S, Branchereau S, Taque S, Chardot C, Guettier C, Scoazec JY, Fabre M, Brugières L, Zucman-Rossi J. Oncoimmunology. 2019 Mar 28;8(6):e1583547. doi: 10.1080/2162402X.2019.1583547. eCollection 2019.
Genomic Medicine and Implications for Hepatocellular Carcinoma Prevention and Therapy. Dhanasekaran R, Nault JC, Roberts LR, Zucman-Rossi J. Gastroenterology. 2019 Jan;156(2):492-509. doi: 10.1053/j.gastro.2018.11.001. Epub 2018 Nov 4. Review.
Systemic AA Amyloidosis Caused by Inflammatory Hepatocellular Adenoma. Calderaro J, Letouzé E, Bayard Q, Boulai A, Renault V, Deleuze JF, Bestard O, Franco D, Zafrani ES, Nault JC, Moutschen M, Zucman-Rossi J. N Engl J Med. 2018 Sep 20;379(12):1178-1180. doi: 10.1056/NEJMc1805673.
Argininosuccinate synthase 1 and periportal gene expression in sonic hedgehog hepatocellular adenomas. Nault JC, Couchy G, Caruso S, Meunier L, Caruana L, Letouzé E, Rebouissou S, Paradis V, Calderaro J, Zucman-Rossi J. Hepatology. 2018 Sep;68(3):964-976. doi: 10.1002/hep.29884. Epub 2018 Jun 6
Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis. Letouzé E, Shinde J, Renault V, Couchy G, Blanc JF, Tubacher E, Bayard Q, Bacq D, Meyer V, Semhoun J, Bioulac-Sage P, Prévôt S, Azoulay D, Paradis V, Imbeaud S, Deleuze JF, Zucman-Rossi J. Nat Commun. 2017 Nov 3;8(1):1315
Pro-angiogenic gene expression is associated with better outcome on sunitinib in metastatic clear-cell renal cell carcinoma. Beuselinck B, Verbiest A, Couchy G, Job S, de Reynies A, Meiller C, Albersen M, Verkarre V, Lerut E, Méjean A, Patard JJ, Laguerre B, Rioux-Leclercq N, Schöffski P, Oudard S, Zucman-Rossi J. Acta Oncol. 2018 Apr;57(4):498-508. doi: 10.1080/0284186X.2017.1388927. Epub 2017 Nov 2
D Jean, MC Jaurand, F Le Pimpec-Barthes, C Meiller, W Blum, L Quetel. Fundings: LNCC IdF and CIT, Chancellerie des Universités de Paris-Legs Poix
Malignant pleural mesothelioma (MPM) is a rare tumor, with a poor prognosis mainly due to the lack of efficient treatment. It is therefore important to develop new therapies that take into account the heterogeneity of MPM at the molecular level. We have recently defined a molecular classification of MPMs that defines two main groups C1 and C2. A subgroup of C2, with a double mutation in the Hippo, NF2 and LATS2 pathway genes, was identified. The C2 group and the NF2 / LATS2 double mutant subgroup contain MPMs from patients with a very poor prognosis. We focus on four major aims:
(1) Refine the molecular classification of malignant pleural mesothelioma and transfer it to clinic: Integrated multi-omic analysis using our large collection of tumors will allow to identify new tumor subgroups. Identification of specific biomarkers and development of prediction tools should facilitate the implementation of this classification to clinic.
(2) Determine the mechanisms of mesothelial carcinogenesis: Functional analysis using our cell lines biobank will lead to define the contribution of specific gene alterations and signal pathways to carcinogenesis.
(3) Develop therapeutic strategy: High-content screening and validation using in vitro and in vivo models will be used to study the correlation between anti-tumor compounds sensibility and the molecular phenotype and will constitute a first step toward precision medicine for mesothelioma.
(4) Characterize intra-tumor heterogeneity: Molecular analysis will be performed to explore heterogeneity of tumor samples at different anatomical sites and presence of cancer stem cells.
We performed a genetic and transcriptomic characterization of malignant pleural mesothelioma (MPM) using our tumor biobanks. We identified the first recurrent oncogenic mutation in the TERT promoter and showed this alteration was frequent in MPM of the sarcomatoid subtype (1). Based on transcriptomic data, we defined a robust molecular classification consisting of two groups (C1 and C2) with different molecular profiles, gene alterations, histology subtypes, and survival outcomes. One of the major interests was to separate the epithelioid MPM, the most frequent histologic subtype, according to their survival prognosis (2). Recently, by coupling transcriptomic and genetic analysis, we identified a new specific MPM molecular subgroup (C2LN) characterized by a co-occurring mutation in LATS2 and NF2 tumor suppressor genes. We identified a specific biomarker and highlighted a high sensitivity to mTOR/PI3K/AKT (PF-04691502) inhibitor treatment for this subgroup (3).
Tallet et al, Oncogene, 2014; de Reynies et al… Jean, Clinical Cancer Research, 2014; Tranchant et al, Clinical Cancer Research, 2017
MD, PhD
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