Multiple skin cancers in adults with mutations in the XP-E (DDB2) DNA repair gene.

TO THE EDITOR Xeroderma pigmentosum complementation group E (XP-E) patients exhibit sunlight-induced lentiginous pigmentation without blistering on minimal sun exposure, yet they are prone to develop multiple skin cancers. Only eight XP-E patients have been reported (Bootsma et al., 1970; De WeerdKastelein et al., 1974; Kraemer et al., 1975; Nichols et al., 1996; Rapic et al., 1998; Itoh et al., 1999, 2000; Rapic-Otrin et al., 2003) with mutations in the DDB2 gene (Tang and Chu, 2002; Itoh, 2006), resulting in the loss of UV-damaged DNA-binding protein (UV-DDB) activity (Nichols et al., 2000; Rapic-Otrin et al., 2003) (Table 1). UVDDB is a heterodimer of DDB1 (p127) and DDB2 (p48) (Keeney et al., 1994; Kazantsev et al., 1996) that binds with high affinity to DNA damaged by UV and is involved in initiation of global genome nucleotide excision repair (GG-NER) (Sugasawa, 2010). We identified four adult XP-E patients from three kindreds with large numbers of skin cancers (Table 1). Patients’ written, informed consent was obtained. The Declaration of Helsinki guidelines were followed and all necessary institutional approvals were obtained. Patient XP1GO, 45 years old, in family A from Germany never experienced a blistering sunburn (Figure 1a). Diagnosed with XP at age 22, he works as a train conductor. His first tumor was removed at age 12. He had 4400 basal cell carcinomas (BCCs) and squamous cell carcinoma (SCCs) and 6 melanomas treated by age 30, and now he develops B20 skin cancers per year. He has no neurological abnormalities. Patient XP37BE is a 45-year-old Caucasian female of Dutch ancestry in family B living in the western United States (Figure 1b). She denies ever having a blistering sunburn. She developed a keratoacanthoma on her face at 7 years and was diagnosed with XP. XP37BE has had 4300 BCC and SCC skin cancers but no melanomas. She has no neurological abnormalities. Patient XP66BE is a 43-year-old brother of XP37BE. He was diagnosed with XP at age 4 at the same time his older sister was diagnosed and exhibits similar clinical symptoms, yet, milder because of improved sun protection. Patient XP408BE is a 53-year-old Caucasian female in family C from the eastern United States (Figure 1c). She had no sunburns and tanned easily, but did experience significant photophobia. At age 14, she was found to have multiple skin cancers (BCCs and SCCs) on her face and a diagnosis of XP was made. She has no XP neurological abnormalities. All cells were either established at the Human Genetic Mutant Cell Repository, the NCI Repository, or in the Department of Dermatology, Goettingen, Germany. Plasmid host cell reactivation assay was performed for cellular DNA repair capacity measurement (Emmert et al., 2000). The cells were transfected with a UV-treated plasmid containing a reporter (luciferase) gene (pCMVLuc). Compared with normal and XP variant cells, XP1GO, XP37BE, XP66BE, and XP408BE/ GM01389 cells had a reduced level of luciferase expression whereas severe XP-B control cells had an even lower level (data not shown). To determine the complementation group we cotransfected the UV-irradiated pCMVLuc with plasmids that carry cloned wildtype XP complementary DNA (cDNA). Only co-transfection of the DDB2 cDNA resulted in markedly enhanced reporter gene activities (data not shown). Human primary XP-E fibroblasts have been reported to show abnormally low or undetectable levels of p53 and its downstream-regulated proteins (Hwang et al., 1999; Itoh et al., 2003; Itoh, 2006). In agreement with this observation, the intensities of p53 and p21 bands were reduced B60–80% and 40–60%, respectively, in untreated XP37BE, XP66BE, and XP408BE/GM01389 cells (ECL Abbreviations: BCC, basal cell carcinoma; cDNA, complementary DNA; GG-NER, global genome nucleotide excision repair; SCC, squamous cell carcinoma; SNP, single-nucleotide polymorphism STR, short tandem repeat; UV-DDB, UV-damaged DNA-binding protein; XP-E, xeroderma pigmentosum complementation group E