The basal layer in human squamous tumors harbors more UVA than UVB fingerprint mutations: a role for UVA in human skin carcinogenesis.
We hypothesized that a substantial portion of the mutagenic alterations produced in the basal layer of human skin by sunlight are induced by wavelengths in the UVA range. Using laser capture microdissection we examined separately basal and suprabasal keratinocytes from human skin squamous cell carcinomas and premalignant solar keratosis for both UVA- and UVB-induced adduct formation and signature mutations. We found that UVA fingerprint mutations were detectable in human skin squamous cell carcinomas and solar keratosis, mostly in the basal germinative layer, which contrasted with a predominantly suprabasal localization of UVB fingerprint mutations in these lesions. The epidermal layer bias was confirmed by immunohistochemical analyses with a superficial localization of cyclobutane thymine dimers contrasting with the localization of 8-hydroxy-2'-deoxyguanine adducts to the basal epithelial layers. If unrepaired, these adducts may lead to fixed genomic mutations. The basal location of UVA-rather than UVB-induced DNA damage suggests that longer-wavelength UVR is an important carcinogen in the stem cell compartment of the skin. Given the traditional emphasis on UVB, these results may have profound implications for future public health initiatives for skin cancer prevention.
Agar
Nita S
NS
Dermatology Research Unit, Melanoma and Skin Cancer Research Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, University of Sydney, Sydney NSW 2006, Australia.
Halliday
Gary M
GM
Barnetson
Ross StC
RS
Ananthaswamy
Honnavara N
HN
Wheeler
Mark
M
Jones
Alexandra M
AM
D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D006151:Guanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D009154:Mutation; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays
D016159:Tumor Suppressor Protein p53; D006151:Guanosine; C046215:8-hydroxyguanosine