The French Cohort of DNA Repair-Deficient Xeroderma Pigmentosum Patients: Risk of Hematological Malignancies

Xeroderma pigmentosum (XP) is a rare genetic disorder characterized by a high incidence of skin cancers. These patients are deficient in nucleotide excision repair caused by mutations in one of the 7 XP genes.

We diagnosed 181 XP patients using UV-induced DNA repair measurements and/or DNA sequencing from 1982 to 2022 in France.

As all XP patients, the French ones are very sensitive to UV exposure but since they are usually very well protected, they develop relatively few skin cancers. A majority of French XP patients originate from North Africa and bear a founder mutation on the XPC gene. The striking discovery is that these patients are at a very high risk to develop aggressive and lethal internal tumors such as hematological malignancies (more than a 100-fold risk compared to the general population for myelodysplasia/leukemia) with a median age of death of 25 years, and brain, gynecological, and thyroid tumors with even lower median ages of death. The high mutation rates found in XP-C internal tumors allow us to think that these XP patients could be successfully treated by immunotherapies. A full analysis of the molecular origins of these DNA repair-deficient tumors is discussed. Several explanations for this high predisposition risk are proposed.

As the age of the XP population is increasing due to better photo-protection, the risk of lethal internal tumors is a new Damocles sword that hangs over XP-C patients. This review of the French cohort is of particular importance for alerting physicians and families to the prevention and early detection of aggressive internal tumors in XP patients.