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bioRxiv · 10.1101/2020.07.13.200667

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

Yurchenko, A. A.·Padioleau, I.·Matkarimov, B. T.·Soulier, J.·Sarasin, A.·Nikolaev, S.
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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). However, the genetic mechanisms of non-skin cancers in XP-C patients remain unexplored. In this study, we analyzed a unique collection of internal XP-C tumor genomes including 6 leukemias and 2 sarcomas. We observed an average of 25-fold increase of mutation rates in XP-C vs. sporadic leukemia which we presume leads to its elevated incidence and early appearance. In all XP-C tumors predominant mutational process is characterized by a distinct mutational signature, highlighting a specific mutational pattern in the context of GG-NER deficiency. We observed 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 leading to internal cancers.

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Yurchenko, A. A., Padioleau, I., Matkarimov, B. T., Soulier, J., Sarasin, A., Nikolaev, S.. 2020-07-14. XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature. https://doi.org/10.1101/2020.07.13.200667

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