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    Genomics and epigenetics of rare tumors

      Team leader

     

    Our main research projects are dedicated to the study of rare tumor-predisposition syndromes (including neurofibromatoses) and their associated cancerous (malignant) and noncancerous (benign) tumors. Our team is interested in (1) the genetic and cellular mechanisms involved in the development of these pathologies, and (2) the genomics and therapeutic targeting of the associated tumors.

     

    Objectives

    The main interests of our group are:

    1. The study of genetics and epigenetics of tumor-predisposition disorders. We aim at understanding the mechanisms underlying the variable expressivity (study of genotype-phenotype correlations, and identification of modifier genes) and the genetic heterogeneity of rare hereditary tumor syndromes, including neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis. More recently, the team has initiated a research project dedicated to digestive tumor predisposition syndromes, including Peutz-Jeghers syndrome and polymerase proofreading-associated polyposis (PPAP). The team develops high-throughput functional genomic assays to interpret missense mutations in the POLE gene causative of PPAP;
    2. The functional characterization of NF1-driven tumors to identify the key drivers of tumorigenesis, and their targeting, through pharmacological and genetic screening.

     

    Main Publications

    • Hamzaoui N, Alarcon F, Leulliot N, Guimbaud R, Buecher B, Colas C, Corsini C, Nuel G, Terris B, Laurent-Puig P, Chaussade S, Dhooge M, Madru C, Clauser E. Genetic, structural, and functional characterization of POLE polymerase proofreading variants allows cancer risk prediction. Genet Med. 2020;22(9):1533-1541.
    • Wassef M, Luscan A, Aflaki S, Zielinski D, Jansen PWTC, Baymaz HI, Battistella A, Kersouani C, Servant N, Wallace MR, Romero P, Kosmider O, Just PA, Hivelin M, Jacques S, Vincent-Salomon A, Vermeulen M, Vidaud M, Pasmant E*, Margueron R*. EZH1/2 function mostly within canonical PRC2 and exhibit proliferation-dependent redundancy that shapes mutational signatures in cancer. Proc Natl Acad Sci U S A. 2019;116(13):6075-6080. *corresponding authors
    • Lobón-Iglesias MJ, Laurendeau I, Guerrini-Rousseau L, Tauziède-Espariat A, Briand-Suleau A, Varlet P, Vidaud D, Vidaud M, Brugieres L, Grill J, Pasmant E. NF1-like optic pathway gliomas in children: clinical and molecular characterization of this specific presentation. Neurooncol Adv. 2019;2:i98-i106.
    • D'Angelo F, Ceccarelli M, Tala, Garofano L, Zhang J, Frattini V, Caruso FP, Lewis G, Alfaro KD, Bauchet L, Berzero G, Cachia D, Cangiano M, Capelle L, de Groot J, DiMeco F, Ducray F, Farah W, Finocchiaro G, Goutagny S, Kamiya-Matsuoka C, Lavarino C, Loiseau H, Lorgis V, Marras CE, McCutcheon I, Nam DH, Ronchi S, Saletti V, Seizeur R, Slopis J, Suñol M, Vandenbos F, Varlet P, Vidaud D, Watts C, Tabar V, Reuss DE, Kim SK, Meyronet D, Mokhtari K, Salvador H, Bhat KP, Eoli M, Sanson M, Lasorella A, Iavarone A. The molecular landscape of glioma in patients with Neurofibromatosis 1. Nat Med. 2019;25(1):176-187.
    • Mandati V, Del Maestro L, Dingli F, Lombard B, Loew D, Molinie N, Romero S, Bouvard D, Louvard D, Gautreau AM, Pasmant E, Lallemand D. Phosphorylation of Merlin by Aurora A kinase appears necessary for mitotic progression. J Biol Chem. 2019;294(35):12992-13005.
    • Tlemsani C, Pécuchet N, Gruber A, Laurendeau I, Danel C, Riquet M, Le Pimpec-Barthes F, Fabre E, Mansuet-Lupo A, Damotte D, Alifano M, Luscan A, Rousseau B, Vidaud D, Varin J, Parfait B, Bieche I, Leroy K, Laurent-Puig P, Terris B, Blons H, Vidaud M, Pasmant E. NF1 mutations identify molecular and clinical subtypes of lung adenocarcinomas. Cancer Med. 2019;8(9):4330-4337.
    • Shackleford G, Sampathkumar NK, Hichor M, Weill L, Meffre D, Juricek L, Laurendeau I, Chevallier A, Ortonne N, Larousserie F, Herbin M, Bièche I, Coumoul X, Beraneck M, Baulieu EE, Charbonnier F, Pasmant E, Massaad C. Involvement of Aryl hydrocarbon receptor in myelination and in human nerve sheath tumorigenesis. Proc Natl Acad Sci U S A. 2018;115:E1319-E1328.
    • Pasmant E, Gilbert-Dussardier B, Petit A, de Laval B, Luscan A, Gruber A, Lapillonne H, Deswarte C, Goussard P, Laurendeau I, Uzan B, Pflumio F, Brizard F, Vabres P, Naguibvena I, Fasola S, Millot F, Porteu F, Vidaud D, Landman-Parker J, Ballerini P. SPRED1, a RAS MAPK pathway inhibitor that causes Legius syndrome, is a tumour suppressor downregulated in paediatric acute myeloblastic leukaemia. Oncogene 2015;34:631-8.
    • De Raedt T, Beert E*, Pasmant E*, Luscan A, Brems H, Ortonne N, Helin K, Hornick JL, Mautner V, Kehrer-Sawatzki H, Clapp W, Bradner J, Vidaud M, Upadhyaya M, Legius E, Cichowski K. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature 2014;514:247-51. *equal contribution
    • Luscan A, Shackleford G, Masliah-Planchon J, Laurendeau I, Ortonne N, Varin J, Lallemand F, Leroy K, Dumaine V, Hivelin M, Borderie D, De Raedt T, Valeyrie-Allanore L, Larousserie F, Terris B, Lantieri L, Vidaud M, Vidaud D, Wolkenstein P, Parfait B, Bieche I, Massaad C, Pasmant E. The activation of the WNT signaling pathway is a Hallmark in neurofibromatosis type 1 tumorigenesis. Clin Cancer Res. 2014;20:358-71.

     

     

    Team’s news

    • Team members are involved in the development and management of the NGS platform shared between the Cochin hospital and the Institut Cochin. The current Cochin NGS Platform launched in March 2012. The first NGS sequencer was acquired thanks to research funds (CAP NF Foundation). In 2013, a tripartite operating agreement was signed between Université de Paris, AP-HP, and INSERM. In 2014, the NGS Platform was labelled by the Université de Paris.
    • Béatrice Parfait is the Manager of the cell bank (CRB) of the Cochin hospital
    • The team is actively participating to the French and European NF network that organized the first global NF meeting in Paris in 2018 (600 participants)
    • Team members participate to regular teaching courses in: Pharmacy (DGFSP2, DGFSP3, DU de médecine génomique), Medicine (DGFSM2, DGFSM3, Parcours d’initiation à la recherche), Science (L2, L3, M1, M2) faculties.

     

     

    Funding

    The team benefits from recurrent financial supports the CAP NF Foundation. The CAP NF Foundation notably provided a financial support for the installation of the team at the Cochin Institute.

    Funding for the study of NF1-associated tumros: The project to identify synthetic lethality with NF1 loss-of-function has been supported since 2019 by The Gilbert Family Foundation's Gene Therapy Initiative; The CARPEM Projet Innovation 2020 grant supports the development of spatial transcriptomic approaches for the study of intra-tumoral heterogeneity of malignant nerve sheaths tumors with mutations in the transcriptional repressor PRC2; The Projet Émergence en Recherche 2020 of IdEx Université de Paris supports the study of the LXRβ pathway for new treatments of neurofibromas.

    Our project of high-throughput functional study of mutations in the exonuclease domain of the DNA polymerase POLE is supported by an Emergence 2020 grant of the Cancéropôle Île-de-France.

    Sauver la vie 2020 grant of the Faculté de Médecine de l’Université de Paris supports our project to identify therapeutic targets in non-small cell bronchial carcinomas with somatic NF1 mutations.

     

                  

     

    Recent contributions of the team

    Study of PRC2 implication in NF1-associated malignant peripheral nerve sheath tumorigenesis. We have previously shown that SUZ12 and EED, two subunits of the transcriptional regulator PRC2, were inactivated in these tumors but that EZH2, the main PRC2 catalytic subunit, was never found mutated. We explored this tumor-type specific mutation patterns by using biochemical and genetic approaches on immortalized Schwann cells from human tumor samples, in collaboration with Dr. Raphaël Margueron's team at the Curie Institute (Wassef et al. Proc Natl Acad U S A 2019).

    Characterization of POLE exonuclease domain mutations using yeast fluctuation assays. The team has developed genetic instability tests and showed that POLE missense pathogenic variants lead to an accumulation of mutations in the yeast genome. This efficient approach allowed the interpretation of variants on a case-by-case basis (Hamzaoui et al. Genet Med 2020). The team now aims to develop a high-throughput functional test to simultaneously characterize all possible variants of the exonuclease domain of the POLE gene in a genetic counselling perspective.