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bioRxiv · 10.1101/2025.07.16.665113

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.
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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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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. Uniquely high spontaneous mutational load in blood cells of XP-C patients. https://doi.org/10.1101/2025.07.16.665113

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