Аннотации:
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.