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.
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).
This frameshift mutation in the xeroderma pigmentosum complementation group C gene led to reduced DNA repair with multiple skin cancers and early death.
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.
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.
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.
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 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.