Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair

Abstract

Background: The frequency of cancer, neurologic degeneration and mortality in xeroderma pigmentosum (XP) patients with defective DNA repair was determined in a four decade natural history study.

Methods: All 106 XP patients admitted to the National Institutes of Health from 1971 to 2009 were evaluated from clinical records and follow-up.

Results: In the 65 per cent (n=69) of patients with skin cancer, non-melanoma skin cancer (NMSC) was increased 10,000-fold and melanoma was increased 2000-fold in patients under age 20. The 9 year median age at diagnosis of first non-melanoma skin cancer (NMSC) (n=64) was significantly younger than the 22 year median age at diagnosis of first melanoma (n=38)-a relative age reversal from the general population suggesting different mechanisms of carcinogenesis between NMSC and melanoma. XP patients with pronounced burning on minimal sun exposure (n=65) were less likely to develop skin cancer than those who did not. This may be related to the extreme sun protection they receive from an earlier age, decreasing their total ultraviolet exposure. Progressive neurologic degeneration was present in 24% (n=25) with 16/25 in complementation group XP-D. The most common causes of death were skin cancer (34%, n=10), neurologic degeneration (31%, n=9), and internal cancer (17%, n=5). The median age at death (29 years) in XP patients with neurodegeneration was significantly younger than those XP patients without neurodegeneration (37 years) (p=0.02).

Conclusion: This 39 year follow-up study of XP patients indicates a major role of DNA repair genes in the aetiology of skin cancer and neurologic degeneration.

Figure 1

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 SCC or keratoacanthoma grew on her upper lip and a pre-cancerous lesion appeared on her forehead. C) Northern African patient XP393BE (XP-C) [32] 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) [45] 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 use of a hearing aid.

Figure 2

XP skin cancer by age at first skin cancer diagnosis and skin cancer type compared to U.S. general population. A. Proportion of NMSC patients diagnosed at selected ages. B. Proportion of melanoma patients diagnosed at selected ages. Individuals with both NMSC and melanoma were used for both analyses. General population data taken from [48].

Figure 3

Skin cancer and mortality in XP patients. A. Probability of the absence of skin cancers for all XP patients (n=106). At age 12 years, 50% of the patients had been diagnosed with NMSC or melanoma skin cancer (arrows) B. Scatter plot age of diagnosis of first skin cancer in patients with both NMSC and melanoma. NMSC was diagnosed earlier or at the same time as melanoma in 29/31 patients.. C. Probability of the absence of skin cancer stratified by burning phenotype. Patients that “never” burned on minimal sun exposure (n= 38) were significantly more likely to develop NMSC or melanoma skin cancer at an earlier age than those that “always or sometimes” burned (n=65) on minimal sun exposure (p=0.006). D. Probability of the absence of skin cancer stratified by XP complementation group. Patients in complementation groups XP-A, XP-B, XP-D and XP-G developed skin cancer at a significantly older age than those in complementation groups XP-C, XP-E and variant (p=0.009). E. Kaplan Meier curve of xeroderma pigmentosum patient survival compared to US general population. 30% of XP patients had died by age 32. The survival of the XP patients was significantly less than the general population (p<0.001). F. Kaplan Meier curve of xeroderma pigmentosum patient survival stratified by neurologic phenotype. Patients with neurologic degeneration had poorer survival rates than those without neurologic degeneration (p=0.04).