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XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature

Author

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  • Andrey A. Yurchenko

    (INSERM U981, Gustave Roussy Cancer Campus, Université Paris Saclay)

  • Ismael Padioleau

    (INSERM U981, Gustave Roussy Cancer Campus, Université Paris Saclay)

  • Bakhyt T. Matkarimov

    (Nazarbayev University)

  • Jean Soulier

    (University of Paris, INSERM U944 and CNRS UMR7212, Institut de Recherche Saint-Louis, F-75010)

  • Alain Sarasin

    (CNRS UMR9019 Genome Integrity and Cancers, Institut Gustave Roussy, Université Paris-Saclay)

  • Sergey Nikolaev

    (INSERM U981, Gustave Roussy Cancer Campus, Université Paris Saclay)

Abstract

Recent studies demonstrated a dramatically increased risk of leukemia in patients with a rare genetic disorder, Xeroderma Pigmentosum group C (XP-C), characterized by constitutive deficiency of global genome nucleotide excision repair (GG-NER). The genetic mechanisms of non-skin cancers in XP-C patients remain unexplored. In this study, we analyze a unique collection of internal XP-C tumor genomes including 6 leukemias and 2 sarcomas. We observe a specific mutational pattern and an average of 25-fold increase of mutation rates in XP-C versus sporadic leukemia which we presume leads to its elevated incidence and early appearance. We describe a strong mutational asymmetry with respect to transcription and the direction of replication in XP-C tumors suggesting association of mutagenesis with bulky purine DNA lesions of probably endogenous origin. These findings suggest existence of a balance between formation and repair of bulky DNA lesions by GG-NER in human body cells which is disrupted in XP-C patients.

Suggested Citation

  • Andrey A. Yurchenko & Ismael Padioleau & Bakhyt T. Matkarimov & Jean Soulier & Alain Sarasin & Sergey Nikolaev, 2020. "XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19633-9
    DOI: 10.1038/s41467-020-19633-9
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