In 1968 James Cleaver reported defective DNA repair in XP [57
]. At NIH, Jay Robbins then initiated a study to evaluate XP patients; Kenneth Kraemer joined the study in 1971 and has led it for decades. We report an up to 39 year follow-up including 15 patients reported in 1974 [4
] plus additional patients through 2009. We found a >10,000 fold increased risk of NMSC and >2,000 fold increased risk of melanoma under age 20. These rates, which vary somewhat from our earlier studies that included some of these patients [1
], are based on longer follow-up and increased numbers, thus contributing substantially more person years at risk The occurrence of UV type mutations in the tumor suppressor genes p53 in NMSC [58
] and PTEN in melanomas [59
] provide molecular evidence of a direct effect of UV exposure in skin cancer in XP patients. Compared to the general population [48
], the XP patients had a 58-year reduction in age at first NMSC, and a 33-year reduction in age at first melanoma. As in the general population, we found that the anatomic site distribution of NMSC in the XP patients was different from that of melanomas [3
]. These differences suggest differences in mechanisms of carcinogenesis between NMSC and melanoma and emphasizes the importance of DNA repair in the protection against NMSC. Indeed, we found that XP-C patients with only a few percent of normal XPC
mRNA resulting from a splice lariat mutation have a lower frequency of NMSC skin cancer than other XPC patients with different splice mutations leading to undetectable levels of XPC
Acute ultraviolet (UVB) exposure of the skin produces sunburn, an inflammatory response with erythema and blistering characterized histologically by a mixed dermal neutrophilic and lymphocytic infiltrate [65
]. In the general population sunburning is a skin cancer risk factor [66
]. Surprisingly, 38 of the XP patients reported never burning but these XP patients were more likely to be diagnosed with skin cancer at an earlier age than the 61% who had a history of always/sometimes burning on minimal sun exposure. This may be partly related to early initiation of rigorous sun protection because XP patients often experience severe blistering sunburn on minimal exposure () (primarily in XP-A and XP-D). XP patients in complementation groups XP-A, XP-B, XP-D and XP-G (those with higher frequency of neurologic disease) were more likely to develop skin cancers at a later age than those patients in complementation groups (XP-C, variant) with no neurologic disease. These patients may also have less mobility. Many XP-C patients did not report burning on minimal sun exposure but tan normally and develop freckle-like pigmentation at an early age followed by skin cancer [28
]. Similarly, mice with a defect in the XPC
gene do not burn on minimal UV exposure [67
]. Fibroblasts from XP patients with a history of sunburning on minimal exposure (in XP-A and XP-D) were reported to be more sensitive to killing by UV than fibroblasts from XP patients who did not burn easily [18
]. It is thus possible that transcription coupled DNA repair (which is defective in XP-A and XP-D but not XP-C) [11
] mediated cytokine generation [24
] may play a major role in generation of the inflammatory sunburn response.
The role of pigmentation in protection from skin cancer is complex. In agreement with other studies of A/AA patients [69
], cancers occurred on less pigmented sites, including the anterior tongue, at a greater frequency than in the NHW patients.[1
] This sun-exposed site is an extremely unusual location for tongue neoplasms [72
]. Perhaps the dark skin offers some protection despite defective DNA repair; thus these patients may experience greater sun exposure than lighter skinned patients. The frequency of NMSC in A/AA (3/100,000) is about 100-fold lower than in NHW [73
]. In contrast, in A/AA XP patients the frequency of NMSC (44%) was not significantly different than NHW patients (61%). Thus a normally functioning DNA repair system may provide greater protection from NMSC than the dark pigmentation present in A/AA skin.
The most common cause of death was skin cancer (metastatic melanoma or invasive SCC). Despite an early age of skin cancer diagnosis, ~45% live into their 40’s and the oldest patient died at age 73 years. As reported by others [58
] we found an increased mortality rate from CNS tumors in patients with defects in the XPC
gene who did not have XP neurological degeneration. There is some evidence that these tumors may result from exposure to oxidative damage [58
]. Lung cancer was present in two cigarette-smoking patients which may be a consequence of the hypersensitivity of XP cells to mutagenic effects of components of cigarette smoke [11
Progressive neurologic degeneration, which may have resulted from primary degeneration of previously normally developed neurons [5
], was a major cause of death among the 25% of the susceptible patients (in XP-D, XP-A, XP-G and XP-B). Fibroblasts from XP patients with neurological degeneration were reported to be more sensitive to killing by UV than cells from XP patients without neurological degeneration [18
]. These findings implicate a role for DNA repair in maintenance of the viability of neurons.
Specific variants of the pigmentation related gene, MC1R
, are associated with increased UV-induced erythema response [75
] and increased risk of both melanoma and NMSC [12
] in the general population, and in families with mutations in the melanoma susceptibility gene, CDKN2A
]. In contrast, based on limited data, MC1R
variants do not appear to dramatically affect the risks of skin cancer in individuals with XP.
Patients ascertained for this NIH study may not reflect the general population of XP patients. Many of our patients have been sun protected from very early ages, which could influence their subsequent development of skin cancer. This 39 year study characterizes the major morbidity and mortality of XP and suggests a major role of DNA repair in the etiology of skin cancer and neurologic degeneration.