PD05 Xeroderma pigmentosum complementation group C: a retrospective observational study of 46 patients reveals skin cancer heterogeneity dependent on the level of nucleotide excision DNA repair

Abstract

Xeroderma pigmentosum (XP) is a rare inherited disorder of nucleotide excision repair (NER). There are eight complementation groups (XP-A to XP-G, and XP-J). The reported median age of first nonmelanoma skin cancer (NMSC) is 9 years, and first melanoma 22 years, compared with 67 and 55 years, respectively, in the population overall. XP-C is the most common subtype in Europe, accounting for 30% of all cases. This study was designed to correlate the level of NER (measured as the percentage unscheduled DNA synthesis, UDS) to the age of onset and subtypes of skin cancers in patients with XP-C. A retrospective observational study of all patients with XP-C attending a UK National Service was completed (2011–2026). Genotype, UDS and skin cancer data were extracted from medical records. Forty-six patients with XP-C (28 male; mean age 22.5 years, range 5–73) were included. There was genotypic variability: 42 had nonsense mutations in XPC (mean UDS 14%) and 4 had missense or splice-site mutations with residual protein activity (mean UDS 46%). Patients with XP-C with low UDS typically developed early onset of NMSC (mean age of first skin cancer 13 years; age 6 years in White patients and 18 years in Asian patients), with only a few developing subsequent melanomas. Four patients with milder XP-C with higher UDS typically presented later with melanoma (mean age of first skin cancer 32 years) and relative sparing of NMSC. XP is a unique disease model for ultraviolet radiation-induced DNA damage and repair and skin cancers. Biologically, keratinocytes are short-lived, rapidly cycling cells, whereas melanocyte turnover is measured in decades. In XP-C, keratinocytes accumulate driver mutations very early (TP53 and PTCH1), leading to childhood-­onset NMSC. In milder XP-C, residual repair can be sufficient to delay NMSC for many years, while melanocytes quietly accumulate unrepaired mutations over decades. Melanoma therefore emerges as the first malignancy later in life, without preceding NMSC.