Ultraviolet Radiation Induced Signature Mutations in Photocarcinogenesis

Abstract

The photons of sunlight begin a series of genetic events in skin leading to cancer. UV signature mutations provide an alternative to inherited mutations as a way of identifying genes that are involved in cancer development. They augment epidemiologic and clinical data by serving as molecular evidence for the role of UV radiation in skin carcinogenesis. Signature mutations are present in TP53 and PTCH, two tumor suppressor genes responsible for non-melanoma skin cancer. We review evidence that clones of TP53-mutated cells are present in normal human and murine epidermis exposed to UVB and conclude that, in addition to being a tumorigenic mutagen, sunlight acts as a tumor promoter by favoring the clonal expansion of TP53 mutated cells. These combined actions of sunlight result in normal individuals' carrying a substantial burden of keratinocytes predisposed to cancer. Thus cancer involves both a single-cell problem and a multi-cell problem; in skin cancer, sunlight appears to drive both.

Epidemiologic Evidence for Different Roles of Ultraviolet A and B Radiation in Melanoma Mortality Rates

“…While UVB directly mutates DNA (38), UVA radiation mutates DNA indirectly through free-radical mediated oxidative damage to guanine bases (20). Far more UVA reaches the melanocyte than UVB, based on quantum calculation of wavelength dependence of photons and there is a UVA/UVB photon ratio in solar noon equinoctial sunlight at temperate latitudes in clear sky conditions in clean air of 30-40 UVA photons to each UVB photon (20,45).…”

“…Most attention to date has centered on UVB since it is the cause of solar erythema and is readily absorbed by DNA (15), where it produces signature mutations in TP53 and PTCH, two tumor suppressor genes that are thought to play a role in nonmelanoma skin cancer (38).…”

The dark side of the light: mechanisms of photocarcinogenesis

“…11,12 These bulky DNA lesions can be repaired by the nucleotide excision repair (NER) system. 3,6 If not properly corrected, they are premutagenic by three conceivable models 6,11,[13][14][15][16] : (1) incorporation of T opposite the altered bases by DNA polymerases that treat them as if they were an adenine (A); (2) direct lesion bypass by an error-prone DNA polymerase that incorporates an A opposite a C within the pyrimidine dimer; and (3) deamination of C within the dimer, giving rise to T or the related uracil, followed by "correct" bypass during DNA replication. These errors may precede or occur during DNA replication, and cause C→T transitions (about 70%) or CC→TT tandem mutations (about 10%) that are termed "signature mutations" for UV(B) mutagenesis, namely they are specific to this mutagen.…”

“…3,6,10,15 Several genes involved in skin carcinogenesis carry a UV signature ( Figure 2). Mutations in the tumor suppressor gene p53 are the most common genetic abnormalities found in SCCs and in their precursors actinic keratoses 6,16,17 ; the majority are C→T single-base-transition mutations at dipyrimidine sites, but CC→TT tandems have also been reported. 6,16 Chronically sun-exposed skin also harbors clonal proliferations of epidermal p53 clones, indicating that these mutations are early events in the pathogenesis of UV-induced SCC.…”

“…Mutations in the tumor suppressor gene p53 are the most common genetic abnormalities found in SCCs and in their precursors actinic keratoses 6,16,17 ; the majority are C→T single-base-transition mutations at dipyrimidine sites, but CC→TT tandems have also been reported. 6,16 Chronically sun-exposed skin also harbors clonal proliferations of epidermal p53 clones, indicating that these mutations are early events in the pathogenesis of UV-induced SCC. 6 Genes that encode proteins of the Hedgehog signaling pathway (mostly the tumor suppressor gene Patched [PTCH]), that upregulates antiapoptotic genes when activated, are the most frequently altered in BCCs, 17 and many mutations in this pathway are C→T and CC→TT transitions.…”