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    Polymerase proofreading-associated polyposis

    Principal Investigator

    Nadim Hamzaoui (PA, APHP)



    POLE and POLD1 are the latest additions to a growing list of genes responsible for Mendelian syndromes associated with adenomatous polyposis and colorectal carcinoma. POLE and POLD1 are the major components of DNA polymerases epsilon and delta respectively, which are the main replicases at the replication fork in eukaryotes. Cancers with missense mutations affecting the proofreading exonuclease domains of POLE and POLD1 have a hypermutator, microsatellite-stable molecular phenotype and are responsive to anti-PD1 immunotherapy. Confirmatory studies in yeast have shown that structurally identical missense mutations could to lead to an accumulation of mutations in the genome.


    The group

    • Eric Pasmant (PU-PH, Université de Paris)
    • Marion Dhooge (PH, APHP)
    • Ivan Bièche (PU-PH, Université de Paris)


    Research interests

    We have found several POLE exonuclease domain missense mutations of unknown clinical significance in the germline DNA of patients with familial colorectal cancer and in the tumour DNA of a variety of sporadic cancers. Accurate assessment of the pathogenicity of these variants is of the utmost importance for genetic counselling and therapeutic management. Our objective is to functionally assess all possible missense changes in the POLE exonuclease domain with saturation genome editing in the cognate yeast gene.


    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.

    Vande Perre P, Siegfried A, Corsini C, Bonnet D, Toulas C, Hamzaoui N, Selves J, Chipoulet E, Hoffmann JS, Uro-Coste E, Guimbaud R. Germline mutation p.N363K in POLE is associated with an increased risk of colorectal cancer and giant cell glioblastoma. Fam Cancer. 2019;18(2):173-178.


    Financial supports         

    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.