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Uniquely high spontaneous mutational load in blood cells of XP-C patients

Fan-Huang, G.; Thompson, E. L.; Lee, M.; Sun, S.; Boull, C.; Maguiness, S. M.; Vijg, J.; Niedernhofer, L. J.; Maslov, A. Y.

2025-07-19 genomics
10.1101/2025.07.16.665113 bioRxiv
Show abstract

We discovered a uniquely high spontaneous somatic mutational load in peripheral blood mononuclear cells (PBMCs) of Xeroderma Pigmentosum group C (XP-C) patients, characterized by elevated single nucleotide variants associated with mutation signatures SBS8 and SBS32, as well as an enrichment of single-nucleotide cytosine deletions. This hypermutability was markedly lower in fibroblasts, suggesting a replication-dependent mechanism of mutagenesis due to deficient global genome nucleotide excision repair (GG-NER). Our findings reveal distinct molecular subtypes within XP defined by spontaneous mutational load in normal blood cells and demonstrate that the exceptionally high mutation burden in XP-C leukemia originates from mutations already present prior to malignant transformation.

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