Additionally, we show that, following exposure to UV-B radiation, XPC p53 mutant mice have more severe solar keratosis and suffer accelerated skin cancer compared with XPC mutant mice that are wild-type with respect to p53.
This frameshift mutation in the xeroderma pigmentosum complementation group C gene led to reduced DNA repair with multiple skin cancers and early death.
Here, we have tested the hypothesis that the XPC PAT+ polymorphism is associated with non-melanoma skin cancer using a population-based case control study of skin cancer in New Hampshire (n=1917).
The high incidence of skin cancers in XP-C patients suggests that loss of expression of XPC protein might also provide a selective advantage for initiation and progression of similar cancers in non XP-C patients in the general population.
A small amount of XPC protein was detected at sites of localized ultraviolet (UV)-damaged DNA in XP72TMA cells which then recruited other nucleotide excision repair (NER) proteins.
The XPC protein plays a key role in recognizing DNA damage in nucleotide excision repair, and patients with XPC deficiency have increased incidence of skin cancer and other malignancies.
In the discovery population, genetic variants in the one-carbon metabolism genes phosphatidylethanolamine N-methyltransferase (rs2278952, P for interaction = .004; rs897453, P for interaction = .05) and dihydrofolate reductase (rs1650697, P for interaction = .02), the inflammation gene interleukin 10 (rs3024496, P for interaction =.04), and the skin cancer genes inositol polyphosphate-5-phosphatase (INPP5A; rs1133400, P for interaction = .03) and xeroderma pigmentosum complementation group C (rs2228000, P for interaction = .01) significantly modified the association between arsenic and skin lesions after adjustments for multiple comparisons.
Notably, analysis of genome-wide maps of NER shows that NER is impaired within the DHS centre of active gene promoters, while XPC-deficient skin cancers do not show increased promoter mutation density, pinpointing differential NER as the underlying cause of these mutation hotspots.