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    Team "Genomics and epigenetics of rare tumors "


    The team Genomics and epigenetics of rare tumors has joined the Department Development, Reproduction, Cancer of Institut Cochin on mid-November 2019


    The main research projects of the “Genomics and epigenetics of rare tumors” team are dedicated to the study of rare tumor-predisposition syndromes, in particular neurofibromatosis. The team is interested in (1) the genetic and cellular mechanisms involved in the development of these pathologies and their variable expressivity, and (2) the genomics and therapeutic targeting of the associated noncancerous (benign) and cancerous (malignant) tumors. The main interests of the team are:

    (1) The study of genetic and epigenetic of cancer-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 familial schwannomatosis. More recently, the team has initiated a research activity dedicated to polymerase proofreading-associated polyposis (PPAP) and develops high-throughput functional assays to interpret missense mutations in the PPAP causing gene, namely POLE.

    (2) The functional characterization of NF1-driven tumors to identify the key drivers of tumorigenesis, and the search for therapeutics approaches with the identification of relevant targets by pharmacological and genetic screens.





    What are the 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 Sci 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.


    Team supports 

    The “Genomics and epigenetics of rare tumors” team benefits from recurrent supports of the CAP NF Foundation, a patient association dedicated to neurofibromatosis (). In particular, the CAP NF Foundation participated in the installation of the team at the Institut Cochin by financing the renovation of the team's premises.

    The project dedicated to identification of synthetic lethality with the loss-of-function of the NF1 gene has been supported since 2019 by the Gilbert Family Foundation.

    The project for the high-throughput functional test of POLE mutations is supported by an Emergence 2020 project of the Cancéropôle Île-de-France.


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