Mutagenicity Profile Induced by UVB Light in Human Xeroderma Pigmentosum Group C Cells^†

Abstract

Nucleotide excision repair (NER) is one of the main pathways for genome protection against structural DNA damage caused by sunlight, which in turn is extensively related to skin cancer development. The mutation spectra induced by UVB were investigated by whole‐exome sequencing of randomly selected clones of NER‐proficient and XP‐C‐deficient human skin fibroblasts. As a model, a cell line unable to recognize and remove lesions (XP‐C) was used and compared to the complemented isogenic control (COMP). As expected, a significant increase of mutagenesis was observed in irradiated XP‐C cells, mainly C>T transitions, but also CC>TT and C>A base substitutions. Remarkably, the C>T mutations occur mainly at the second base of dipyrimidine sites in pyrimidine‐rich sequence contexts, with 5′TC sequence the most mutated. Although T>N mutations were also significantly increased, they were not directly related to pyrimidine dimers. Moreover, the large‐scale study of a single UVB irradiation on XP‐C cells allowed recovering the typical mutation spectrum found in human skin cancer tumors. Eventually, the data may be used for comparison with the mutational profiles of skin tumors obtained from XP‐C patients and may help to understand the mutational process in nonaffected individuals.

Retrospective study of efficacy and adverse events of immune checkpoint inhibitors in 22 xeroderma pigmentosum patients with metastatic or unresectable cancers

“…These patients have mutations in genes involved in repairing ultraviolet (UV)induced DNA damage. Because of failure to repair DNA damage, XP patients' cells may harbor large numbers of mutations (2)(3)(4). Their sensitivity to UV results in a >1,000-fold increased risk of skin cancers and 34-fold increased risk of internal tumors (5,6).…”