XPC DEFICIENCY INCREASES RISK OF HEMATOLOGIC MALIGNANCIES THROUGH MUTATOR PHENOTYPE AND CHARACTERISTIC MUTATIONAL SIGNATURE
Loading...
Date
2020-11-17
Authors
Yurchenko, Andrey A.
Padioleau, Ismael
Matkarimov, Bakhyt T.
Soulier, Jean
Sarasin, Alain
Nikolaev, Sergey
Journal Title
Journal ISSN
Volume Title
Publisher
Nature Research
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.
Description
Keywords
Xeroderma Pigmentosum group C, XPC, hematologic malignancies, mutator phenotype, mutational signature, Research Subject Categories::NATURAL SCIENCES
Citation
Yurchenko, A. A., Padioleau, I., Matkarimov, B. T., Soulier, J., Sarasin, A., & Nikolaev, S. (2020). XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature. Nature Communications, 11(1). https://doi.org/10.1038/s41467-020-19633-9