UV damage, DNA repair and skin carcinogenesis.
Skin cancer is unique among human cancers in its etiology, accessibility and the volume of detailed knowledge now assembled concerning its molecular mechanisms of origin. The major carcinogenic agent for most skin cancers is well established as solar ultraviolet light. This is absorbed in DNA with the formation of UV-specific dipyrimidine photoproducts. These can be repaired by nucleotide excision repair or replicated by low fidelity class Y polymerases. Insufficient repair followed by errors in replication produce characteristic mutations in dipyrimidine sequences that may represent initiation events in carcinogenesis. Chronic exposure to UVB results in disruption of the epithelial structure and expansion of pre-malignant clones which undergo further genomic changes leading to full malignancy. Genetic diseases in DNA repair, xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy, show varied elevated symptoms of sun sensitivity involving skin cancers and other symptoms including neurological degeneration and developmental delays. In humans, only xeroderma pigmentosum shows high levels of cancer, but mouse strains, with any of the genes corresponding to these diseases knocked-out, show elevated skin carcinogenesis. The three major skin cancers exhibit characteristic molecular changes defined by certain genes and associated pathways. Squamous cell carcinoma involves mutations in the p53 gene; basal cell carcinoma involves mutations in the PATCHED gene, and melanoma in the p16 gene. The subsequent development of malignant tumors involves many additional genomic changes that have yet to be fully cataloged.
Cleaver
James E
JE
UCSF Cancer Center and Department of Dermatology, Box 0808,University of California, San Francisco, CA 94143-0808, USA. jcleeaver@cc.ucsf.edu
Crowley
Eileen
E
D000818:Animals; D002280:Basal Cell Carcinoma / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication / Q000528:radiation effects; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000150:complications / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D051379:Mice; D008957:Models, Genetic; D016296:Mutagenesis; D012878:Skin Neoplasms / Q000209:etiology* / Q000235:genetics; D014466:Ultraviolet Rays / Q000009:adverse effects*
D004259:DNA-Directed DNA Polymerase