Forty years of research on xeroderma pigmentosum at the US National Institutes of Health

Abstract

In 1968, Dr. James Cleaver reported defective DNA repair in cultured cells from patients with xeroderma pigmentosum. This link between clinical disease and molecular pathophysiology has sparked interest in understanding not only the clinical characteristics of sun sensitivity, damage and cancer that occurred in XP patients but also the mechanisms underlying the damage and repair. While affected patients are rare, their exaggerated UV damage provides a window into the workings of DNA repair. These studies have clarified the importance of a functioning DNA repair system to the maintenance of skin and neurologic health in the general population. Understanding the role of damage in causing cancer, neurologic degeneration, hearing loss and internal cancers provides an opportunity for prevention and treatment. Characterizing complementation groups pointed to the importance of different underlying genes. Studying differences in cancer age of onset and underlying molecular signatures in cancers occurring either in XP patients or the general population has led to insights into differences in carcinogenic mechanisms. The accelerated development of cancers in XP has been used as a model to discover new cancer chemopreventive agents. An astute insight can be a "tipping point" triggering decades of productive inquiry.

Figure 1

XP skin cancer by age at first skin cancer diagnosis and skin cancer type compared to US general population. Upper panel: Proportion of non-melanoma skin cancer (NMSC) patients diagnosed at selected ages. Lower panel: Proportion of melanoma patients diagnosed at selected ages. Individuals with both NMSC and melanoma were used for both analyses. General population data was taken from (37) (Figure from (30)).

Figure 2

XP patients in study. (A) Patient XP420BE complementation group XP-D at 9 months of age with severe blistering erythema of the malar area following minimal sun exposure. Note sparing of her forehead and eyes that were protected by a hat. (B) Patient XP358BE (XP-C) at age 2 years did not sunburn easily but developed multiple hyperpigmented macules on her face. A rapidly growing squamous cell carcinoma (SCC) or keratoacanthomas grew on her upper lip and a pre-cancerous lesion appeared on her forehead. (C) Northern African patient XP393BE (XP-C)(38) at age 23 years with numerous hyperpigmented macules on his face. Nodular basal cell cancer is present on his left nasal root. Pigmented basal cell cancer is present on his left cheek. His eyes show cornea scarring from unprotected sun exposure. (D) Patient XP19BE (XP-A)(39) at age 35 years with neurological degeneration. He has numerous hyperpigmented macules on sun exposed areas of his face and neck. Progressive sensorineural deafness requires the use of a hearing aid (Figure from (30)).