UV radiation and skin cancer

Skin cancer incidence

Skin cancer is the most common neoplasm in Caucasians in the United States, with a lifetime risk nearly equal to that of all other cancers combined [1]. The annual incidence of non-melanoma skin cancer (basal cell carcinoma or squamous cell carcinoma) was estimated at 900 000 to 1.2 million for the United Sates in 1994, which is up from 600 000 just 5 years earlier [2]. Although the incidence of melanoma is considerably lower, its more aggressive biological behaviour (responsible for 7500 deaths in the United States in 1994) has also been considered reason for concern [3].

For more information see:

Introduction to skin cancer
Skin cancer information

Relationship between UV exposure and skin cancer

Extensive clinical and epidemiological evidence indicates that exposure to the ultraviolet (UV) component of sunlight is the main causative factor in the development of skin cancers [4-7]. It is believed that decreases in stratospheric ozone (which shields the earth from short wavelength UV) [8], socio-economic factors that permit more time for outdoor leisure activities, and current societal standards which consider tanned skin attractive account (at least in part) for the recent increases in cutaneous malignancies by increasing cutaneous UV exposure [9].

The UV spectrum, types of damage, and relative cancer risk

The biological effects and relative occurrence of different UV wavelengths, varies considerably across the UV spectrum. This has led to the division of the spectrum into three ranges on the basis of wavelength (summarised in table below): UV-A (320-400 nm), UV-B (280-320 nm) and UV-C (200-280 nm). UV-A (also referred to as long wave or near-UV) can penetrate as deep as the basal layer and capillary bed of exposed skin. It induces primarily oxidative DNA damage to various cellular components, however as damaged proteins and lipids are readily degraded and resynthesised, damage to DNA is thought to have the most significant consequences [10]. Although UV-A accounts for almost 95% of UV radiation to reach the surface of the earth, it accounts for less than 25% of the associated skin cancer risk [11]. However, it is believed to play a principal role in photoaging of exposed skin [12, 13].

At the other end of the spectrum is UV-C (also referred to as short wave, or far UV) which is directly absorbed by DNA and results in inappropriate bonding between adjacent pyrimidines. Although exposure to UV-C is highly carcinogenic in lab settings, it does not contribute to skin cancer in the general population as solar UV-C is almost completely absorbed by ozone in the earth's stratosphere and does not reach the surface of the earth [14]. Rather, it is UV-B (280-320 nm) that is calculated to account for greater than 75% of the skin cancer risk, even though it comprises only about 5% of terrestrial UV [11]. Although UV-B also produces oxidative intermediates, it is its ability to induce direct UV-C-like DNA damage that is responsible for its carcinogenic potential [15, 16].

	UV-A	UV-B	UV-C
wavelengths	320-400 nm	280-320 nm	200-280 nm
% of sunlight reaching earth's surface	95 %	5 %	~ 0 %
associated cancer risk	25 %	75 %	~ 0 %
type of damage induced	oxidative	oxidative and direct photodamage	direct photodamage

Oxidative DNA damage

Probably the most abundant source of DNA alterations arises from the constant exposure to reactive oxygen species. These species are formed continually as by-products of cellular metabolism, although they can also be induced by exogenous sources such as ionising radiation, long wavelength ultraviolet radiation and H₂O₂. It has been estimated that every day as many as 10 000 oxidation reactions cause DNA damage in one human cell [17]. This damage includes DNA single strand and double-strand breaks, abasic sites, DNA-protein crosslinks and over 35 different base modifications [18-23]. Oxidative DNA damage has been implicated in the etiology of ageing, as well as that of cancer [24-26].

Oxidative DNA base damage is primarily repaired by the base excision repair pathway.

DNA photoproducts induced by UV-B and UV-C

The DNA damage induced by UV-B and UV-C form two major classes of pyrimidine photoproducts: cyclobutane pyrimidine dimers (CPDs) and (6-4) pyrimidine-pyrimidone photoproducts (6-4 PP) [27]. These photoproducts are formed in DNA at approximately 3:1 proportions [28], both distort normal base-pair stacking (although this is considerably more pronounced for the 6-4 PP, resulting in a bending of the DNA by 44^o compared to only 7-9^o for a CPD [29-31] (see Figure)), and both have been implicated in neoplastic transformation [28, 32, 33].

The accumulation of damaged DNA has considerable consequences for living organisms. Both CPDs and 6-4 PPs (as well as some forms of oxidative base damage) can directly inhibit transcription and DNA replication processes [34-37]. When replication of damaged DNA does occur, there is an increased likelihood of misincorporating nucleotides into the nascent strand, giving rise to base substitutions [38].

CPDs and 6-4 PPs are primarily repaired by nucleotide excision repair.

However, additional alternative repair mechanisms exist in some species.

References

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