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    Study of the involvement of the NF1 gene in sporadic tumorigenesis

    Principal Investigator

    Camille Tlemsani
    Contact: camille.tlemsani@parisdescartes.fr

    Ivan Bièche
    Contact: ivan.bieche@parisdescartes.fr

     

    Objective

    NF1 is a major tumor suppressor gene encoding neurofibromin, a RAS-GAP (GTPase activating protein) that acts as an inhibitor of the RAS-MAPK pathway by allowing RAS proteins to return to inactive confirmation. NF1 gene alterations and their therapeutic targeting have been little studied in sporadic cancers because NF1 is a long gene with many pseudogenes and no mutation hot spot.

     

    The group

    • Eric Pasmant (PU-PH, Université de Paris)
    • Cyril Burin des Roziers (PH, APHP)
    • Ingrid Laurendeau (IE, Université de Paris)

     

    Research interests

    We characterized genetic alterations in the NF1 gene in a cohort of non-small cell lung carcinomas (NSCLC) using a targeted NGS approach to confirm NF1 involvement and to characterize genotype/phenotype correlations. A NF1 genetic alteration was found in 24/137 (17%) samples (Tlemsani et al., 2019). Our objectives are to understand the functional consequences of NF1 inactivation and to identify new potential therapeutic targets in NF1-mutated bronchial carcinomas which represent a distinct subtype of cancer. We have developed cellular models of NF1-mutated bronchial carcinoma, using the CRISPR Cas9 genome editing technique. Our hypothesis is that NF1 mutations in the context of NSCLC carcinogenesis could cause cellular vulnerabilities that constitute therapeutic targets by synthetic lethality. We explore these synthetic lethalities with NF1 mutations using pharmacological and genetic approaches

    In addition to bronchial tumors, our team is also interested in the characterization of NF1 mutations and more broadly of negative regulators of the RAS-MAPK pathway in pediatric acute lymphoblastic B leukemia (ALL-B). The activation of the main effectors of the pathway is well described but the alterations of the regulators are still poorly understood. Our project is to characterize (1) the transcriptome variations of a panel of negative regulators of the pathway, using a targeted transcriptomic study, and (2) the genetic alterations of these effectors in a large cohort of pediatric B-ALLs (including matched relapse samples), using a targeted NGS sequencing study.

     

    Main publications

    • 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.
    • Tlemsani C, Pongor L, Elloumi F, Girard L, Huffman KE, Roper N, Varma S, Luna A, Rajapakse VN, Sebastian R, Kohn KW, Krushkal J, Aladjem MI, Teicher BA, Meltzer PS, Reinhold WC, Minna JD, Thomas A, Pommier Y. : SCLC-CellMiner: A Resource for Small Cell Lung Cancer Cell Line Genomics and Pharmacology Based on Genomic Signatures. Cell Rep. 2020;33(3):108296.
    • Tlemsani C, Leroy K, Gimenez-Roqueplo AP, Mansuet-Lupo A, Pasmant E, Larousserie F, Boudou-Rouquette P, Vidaud M, Cadranel J, Blons H, Goldwasser F, Laurent-Puig P. Chemoresistant pleomorphic rhabdomyosarcoma: whole exome sequencing reveals underlying cancer predisposition and therapeutic options. J Med Genet. 2020;57(2):104-108.
    • Tlemsani C, Pasmant E, Boudou-Rouquette P, Bellesoeur A, Even J, Larousserie F, Reyes C, Gentien D, Alexandre J, Vidaud M, Anract P, Leroy K, Goldwasser F. BRCA2 Loss-of-Function and High Sensitivity to Cisplatin-Based Chemotherapy in a Patient With a Pleomorphic Soft Tissue Sarcoma: Effect of Genomic Medicine. Am J Med Sci 2018;356(4):404-407

     

    Financial supports

    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 is supported.

    The project to characterize the negative mediators of the RAS-MAPK pathway involved in pediatric ALL-B has received the support of Société Française de Lutte contre les Cancers et Leucémies de l'Enfant et de l'Adolescent (SFCE).