Characteristics of UV Radiation
Fate and Transport of UV Radiation
Monitoring UV Radiation
Methods of Measurement of Human Exposure
Prevention of Exposure
Absorption, Distribution, Metabolism
Sites of Toxicity
Biomarkers of Disease
Molecular Mechanism of Action
Risk Assessment and Risk Management
Molelcular Mechanism of Action
Genes Damaged by UV Radiation
Ultraviolet (UV) radiation is known to cause distinct mutations in keratinocytes that ultimately contribute to the development of the nonmelanoma skin cancers, which include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The process by which these mutations are introduced begins with the reaction of UV photons with cellular DNA (1). As photons are absorbed by DNA molecules, an excited state is produced which allows for the rearrangement of electrons resulting in the formation of photoproducts. There are two photoproducts, both of which are dipyrimidine structures, believed to be responsible for most of the carcinogenic effects of UV radiation. These two photoproducts, cyclobutane pyrimidine dimer (CPD) and 6-4 pyrimidine pyrimidone, are caused by exposure to UV-B radiation. CPD is more common than 6-4 pyrimidine-pyrimidone and is thought to account for approximately 85% of primary lesions in UV-irradiated DNA. The photoproducts interfere with DNA replication if not repaired and cause specific mutations in DNA. The specific mutations induced by UV-B in DNA sequences most often include single-base substitutions of cytosine (C) for thymine (T). Double-base changes from CC to TT also occur, but in an order of magnitude less frequently. While the photoproducts that cause UV-B induced base-substitutions have been well characterized, this is not the case for UV-A radiation. However, T to guanine (G) transversions have consistently been found in studies, as well as, double-base changes from TT to GG. UV-A radiation is known to be 10,000 times less mutagenic than UV-B (1). Sunlight is also believed to play an important role in the development of melanoma, but the molecular basis for nonheritable forms of melanoma is incompletely understood. Studies of mutational changes in melanocytic dysplastic nevi, which are often precursors of malignant melanoma, have found C to T transition-type mutations specific to UV radiation (2).
The photoproducts that result from exposure to UV radiation are not a problem so long as they are efficiently repaired, however it is believed that with excessive, chronic exposure to sunlight, the repair pathway in skin cells becomes overwhelmed allowing for photoproducts to persist and be passed on in subsequent rounds of replication. This ultimately leads to transcriptional errors and in some cases cancer. The type of DNA damage caused by UV radiation is repaired via the nucleotide excision repair (NER) pathway (3). This pathways consists of five steps including the following: 1) recognition of DNA lesion, 2) incision of the damaged strand on both sides of the lesion, 3) removal of the damaged oligonucleotide, 4) synthesis of a patch, and 5) ligation of the patch. The importance of this pathway in protecting against skin cancer is illustrated by considering individuals with the hereditary disorder xeroderma pigmentosum (XP). Individuals with XP have a mutation in one of several genes involved in the NER pathway, the pathway involves the products of at least 20 genes, and as a result they have a 2000-fold increased risk of skin cancer (3). In terms of the specific photoproducts, 6-4 pyrimidine-pyrimidone is known to be more mutagenic than CPD, however 6-4 pyrimidine-pyrimidone is repaired 15 times more efficiently than CPD (1).
Genes Damaged by UV Radiation
Tumor Suppressor Gene p53
Targets of DNA damage caused by UV radiation exposure include both proto-oncogenes and tumor suppressor genes. However, mutations in the tumor suppressor gene p53 are thought to play a critical role in the development of precancerous lesions and have been implicated in all types of skin cancer. This gene is also very important for other types of cancer besides skin cancer as mutations in this gene have been found in approximately 50% of all human cancers (4). The p53 gene encodes signaling molecules that are responsible for induction of cell cycle arrest and apoptosis (programmed cell death), checks for cellular growth. As such, p53 plays a role in responding to damage from UV radiation. Proteins encoded by this gene accumulate in the nucleus of cells following exposure to UV. This causes delays in the cell cycle allowing time for DNA repair of UV photoproducts and elimination of damaged keratinocytes that may have acquired premalignant or malignant characteristics by apoptosis. When mutations occur that cannot be repaired, p53 loses these control functions and damaged cells are allowed to replicate. The damaged keratinocytes are thought to acquire increasing resistance to apoptosis as more p53 mutations accumulate with continued exposure to the sun and thus are able to survive multiple cycles of UV exposure (1).
In terms of nonmelanoma skin cancer, mutations of p53 have been found in a high percentage of SCCs and approximately 50% of the BCC tumors that have been studied (1,4). The p53 mutations found in both SCCs and BCCs to date have been predominantly C to T and CC to TT base substitutions implicating UV-B radiation as the causative agent. SCCs are thought to adhere to a multistage model of carcinogenesis, which postulates that precursor cells must acquire successive genetic lesions (or hits) prior to forming tumors (1). This model makes sense for p53 as described above. SCCs are known to transition from precursor lesions, actinic keratoses, where one p53 mutation (or a mutation in a proto-oncogene) has occurred to invasive carcinoma as additional mutations are acquired. In SCCs there is typically a loss of one p53 allele and isolated mutations in the other allele in tumors (1). In BCCs, the mutations tend to cluster in a specific region of the p53 gene in exons 5 to 9 (4). In addition, in BCCs there is no loss of an allele, but mutations tend to be found on both p53 alleles (1).
Mutations can also occur in the p53 gene in some melanomas, however the incidence of these mutations is much less. p53 mutations are detected in less than 25% of melanoma cases and the role these mutations play in melanoma tumorigenesis appears to be different than in nonmelanoma skin cancer (2). In fact, the exact mechanisms of these mutations are unknown. Whereas p53 mutations occur early after exposure to UV radiation in nonmelanoma skin cancer, before the appearance of tumors, p53 mutations are most common in metastatic melanomas (2,3). Studies have reported the presence of p53 mutations in just 1-5% of primary melanomas compared to 11-25% of metastatic melanomas. In dysplastic nevi, precursors of malignant melanoma, p53 mutations have been reported to occur at an even lower frequency of 0-16%. In addition, p53 protein is widely overexpressed in melanomas in late stages in spite of relatively few p53 mutations. There is an inverse relationship between overexpression of the protein product and actual mutations in this gene, which suggests that other genes/proteins related to p53 may alter levels of p53 protein and may therefore play a central role in the progression of melanoma (2).
The ras family of proto-oncogenes has also been implicated as a target for UV-B radiation damage (1,3). Proto-oncogenes are normal genes that when mutated (oncogenes) become active all the time or encode proteins with new functions. The ras proto-oncogenes encode G proteins that hydrolyze guanosine 5-triphosphate and mediate cell signaling for many growth factor receptors. When damaged by UV radiation, a ras proto-oncogene becomes an oncogene, which produces a mutant protein that no longer hydrolyzes guanosine 5-triphosphate and cell growth is now allowed in the absence of growth factors. Cells with mutations in ras have an initiated phenotype and are thought to play a role in the early event of skin carcinogenesis. UV-B specific mutations have been found in ras genes in some human BCCs and SCCs. Amplification of ras genes has been seen in individuals with XP (1).
PTCH Tumor Suppressor Gene
PTCH is the second tumor suppressor gene implicated in BCC. It is the gene responsible for nevoid basal cell carcinoma (NBCCS), which is an autosomal dominant syndrome characterized by multiple BCCs at an early age. However, it has also been implicated in sporadic BCCs. Somatic mutations in the PTCH gene have been identified in 20-30% of sporadic BCCs that have been studied. The mutations that occur in this gene in sporadic cases of BCCs are very similar to those seen in p53. They are UV-B specific C to T and CC to TT base substitutions (4).
Since only 25% of melanomas are thought to involve mutations in the p53 tumor suppressor gene, a number of other genes have implicated in the development of melanoma. Some of these include the CMM1 gene on chromosome 1p36, tumor suppressor gene p16 on chromosome 9p21, and the cyclin dependent kinase gene CDK4 on chromosome 12q14, as well as, a number of genes associated with the p53-related pathways (2,3).
1. Grossman D, Leffell D. The molecular basis of nonmelanoma skin cancer. Arch Dermatol. 1997; 133: 1263-1270.
2. Hussein MR, Haemel AK, Wood GS. p53-related pathways and the molecular pathogenesis of melanoma. European Journal of Cancer Prevention. 2003; 12: 93-100.
3. Kane AB, Kumar V. (1999). Environmental and Nutritional Pathology. In Cotran RS, Kumar V, Collins T. (Eds.), Robbins Pathologic Basis of Disease- Sixth Edition (pp. 403-458). Philadelphia, PA: W.B. Saunders Company.
4. Ratner D, Peacocke M, Zhang H, Ping X, Tsou H. UV-specific p53 and PTCH mutations in sporadic basal cell carcinoma of sun-exposed skin.
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