High cancer-associated mutational burden in normal blood of xeroderma pigmentosum group C, but not groups A, D, or F

Xeroderma pigmentosum (XP) is a rare autosomal recessive congenital syndrome characterized by defective nucleotide excision repair (NER), leading to extreme photosensitivity and a strong predisposition to skin cancer. One of the 8 complementation groups, XP complementation group C (XP-C), is defective specifically in the global genome component of NER and presents not only with increased skin cancer but also with hematologic cancers. Using error-corrected single-molecule sequencing, we show a uniquely high spontaneous somatic mutational load in peripheral blood mononuclear cells (PBMCs) of patients with XP-C but not in those of patients from other XP complementation groups (XP-A, XP-D, and XP-F). The hypermutability observed in XP-C was markedly lower in fibroblasts than in PBMCs. The XP-C mutational profile was characterized by elevated single-nucleotide variants (SNVs) associated with mutational signatures SBS5, SBS8, and SBS32, as well as an enrichment of single-nucleotide cytosine deletions, with SNV profiles closely mirroring those found in XP-C leukemias. These findings indicate that a cancer-like mutation burden is already present in normal lymphocytes before malignant transformation, revealing distinct molecular subtypes within XP defined by spontaneous mutational load in normal blood cells.