Xeroderma pigmentosum variant (XP‐V) is a rare genetic disease, characterized by some sunlight sensitivity and predisposition to cutaneous malignancies. We described clinical and genetic features of the largest collection ever published of 23 XP‐V patients (ages between 21 and 86) from 20 unrelated families. Primary fibroblasts from patients showed normal nucleotide excision repair but UV‐hypersensitivity in the presence of caffeine, a signature of the XP‐V syndrome. 87% of patients developed skin tumors with a median age of 21 for the first occurrence. The median numbers of basal‐cell carcinoma was 13 per patient, six for squamous‐cell carcinoma, and five for melanoma. XP‐V is due to defects in the translesion‐synthesis DNA polymerase Polη coded by the POLH gene. DNA sequencing of POLH revealed 29 mutations, where 12 have not been previously identified, leading to truncated polymerases in 69% of patients. Four missense mutations are correlated with the protein stability by structural modeling of the Polη polymerase domain. There is a clear relationship between the types of missense mutations and clinical severity. For truncating mutations, which lead to an absence of or to inactive proteins, the life‐cumulated UV exposure is probably the best predictor of cancer incidence, reinforcing the necessity to protect XP‐Vs from sun exposure.

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Background: Xeroderma pigmentosum (XP) is a rare, autosomal, recessive DNA repair-deficiency disorder with a frequency of 1–3 per million livebirths in Europe and USA but with higher frequencies in isolated islands or in countries with a high level of consanguinity. XP is characterized by high incidence of skin cancers on sun-exposed sites. Recent improvement in life expectancy of XP patients suggests an increased risk of frequently aggressive and lethal internal tumors. Our purpose was to quantify relative risks of internal tumor development for XP patients by tumor type, XP-subtype, patients’ ages and ethnicity through comparison with the US general population.Methods: We analyzed four independent international well-characterized XP cohorts (from USA, UK, France and Brazil) with a total of 434 patients, where 11.3% developed internal tumors and compared them to the American general population. We also compiled, through PubMed/Medline, a dataset of 89 internal tumors in XP patients published between 1958 and 2020.Results: In the combined 4-XP cohort, relative risk of internal tumors was 34 (95% confidence interval (CI) 25–47) times higher than in the general population (p-value = 1.0E−47) and tumor arose 50 years earlier. The XP-C group was at the highest risk for the 0–20 years old-patients (OR = 665; 95% CI 368–1200;p-value = 4.3E−30). The highest risks were observed for tumors of central nervous system (OR = 331; 95% CI 171–641;p-value = 2.4E−20), hematological malignancies (OR = 120; 95% CI 77–186;p-value = 3.7E−36), thyroid (OR = 74; 95% CI 31–179;p-value = 1.2E−8) and gynecological tumors (OR = 91; 95% CI 42–193;p-value = 3.5E−12). The type of mutation on theXPCgene is associated with different classes of internal tumors. The majority of French XP-C patients (80%) are originated from North Africa and carried theXPCdelTG founder mutation specific from the South Mediterranean area. The OR is extremely high for young (0–20 years) patients with more than 1300-fold increase for the French XPs carrying the founder mutation.Conclusion: Because the age of XP population is increasing due to better sun-protection and knowledge of the disease, these results are of particular importance for the physicians to help in early prevention and detection of internal tumors in their XP patients. Few preventive blood analyses or simple medical imaging may help to better detect early cancer appearance in this population.