Mechanisms of photocarcinogens

March 1, 2005

Photocarcinogenesis is not simply a story of mutations arising from ultraviolet (UV)-induced pyrimidine dimer formation, according to Chikako Nishigori, M.D., Ph.D., professor and chairman of the division of dermatology at Kobe University Graduate School of Medicine.

Photocarcinogenesis is not simply a story of mutations arising from ultraviolet (UV)-induced pyrimidine dimer formation, according to Chikako Nishigori, M.D., Ph.D., professor and chairman of the division of dermatology at Kobe University Graduate School of Medicine.

"In addition to pyrimidine dimers and other photoproducts, many other factors are involved, including indirect damage caused by UV, and indirect damage caused by inflammatory cells. Also, host immune response plays an important role in photocarcinogenesis."

Initial evidence suggesting an association between UV irradiation and skin cancer came from the following observations:

UV irradiation "UVC has high energy and UVC irradiation links adjacent pyrimidines to form pyrimidine dimers, whereas UVA has lower energy and causes DNA damage indirectly through endogenous photosensitizers," Dr. Nishigori says.

"UVB irradiation not only produces pyrimidine dimers and other photoproducts directly, but also causes DNA damage indirectly in the presence of photosensitizers," he adds.

Photosensitizers absorb and transfer radiation energy and include cellular molecules such as porphyrins, flavins, quinones and nicotinamide adenine dinucleotide (NADH).

UV irradiation links adjacent pyrimidines in a DNA strand to form either cyclobutane thymine dimers or 6-4 photoproducts, in which C-6 of one thymine forms a bond with C-4 of the adjacent thymine. Resolution of these structures can lead to the so-called "UV signature mutation" associated with dipyrimidine sequences, a G:C to T:A mutation. A mutation of this type is known as a transition, defined as a change from one pyrimidine (cytosine or thymine) or purine (guanine or adenine) to the other.

Signature mutations Earlier studies have shown a high incidence (50 percent or greater) of mutations in the p53 gene in non-melanoma skin cancer in Caucasian patients, with the majority of the mutations characterized as "UV signature mutations". A similar mutational spectrum was seen in non-melanoma skin cancer tumors in Japanese patients, both in XP patients and in patients without the genetic disorder.

In Japanese patients, squamous cell carcinomas often arise on covered areas without prior sun exposure. In a study of Japanese patients with skin cancer published earlier, Dr. Nishigori and colleagues compared tumors from sun-exposed areas with tumors from covered areas and identified p53 mutations in 12 tumors from sun-exposed areas and in 11 tumors from covered areas. The two groups differed significantly.

UV signature mutations were detected in 50 percent (six in 12) of tumors from sun-exposed areas but in less than 20 percent (two in 11) of tumors from covered areas.

In a follow-up study, Dr. Nishigori and colleagues induced skin cancers in mice by UV irradiation, established primary tumor cells in vitro and then transfected the tumor cells into golden hamster embryo cells. Molecular changes in ras oncogenes were examined using PCR and Southern blot analysis. The expected "signature mutation" normally associated with pyrimidine dimer formation was observed in some cases, but a surprising finding was the high incidence of G:C to T:A mutations. Mutations of this type are known as transversions, changes from purines (G or A) to pyrimidines (C or T), or vice versa.

Mutagenic effect The G:C to T:A transversions likely arise from the mutagenic effect of free oxygen radicals generated as a result of UV irradiation. Addition of a free oxygen radical can change guanine to 8-hydroxyguanine. In the keto formation as 8-OHdG, it remains paired with cytosine, but conversion to the enol formation allows a bond to form with adenine, resulting in an eventual G:C to T:A transversion.

UV irradiation and photocarcinogenesis are closely associated with cutaneous inflammation.