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 carci...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2004-04, Vol.101 (14), p.4954-4959
Main Authors: Agar, Nita S., Halliday, Gary M., Ross St C. Barnetson, Ananthaswamy, Honnavara N., Wheeler, Mark, Jones, Alexandra M., Setlow, Richard B.
Format: Article
Language:English
Subjects:
Biological Sciences
Carcinoma, Squamous Cell - etiology
Carcinoma, Squamous Cell - genetics
Carcinoma, Squamous Cell - metabolism
Codons
Epidermis
Genetic mutation
Guanosine - analogs & derivatives
Guanosine - metabolism
Humans
Keratinocytes
Medical research
Mutation
Public health
Radiation damage
Skin
Skin cancer
Skin cancers
Skin Neoplasms - etiology
Skin Neoplasms - genetics
Skin Neoplasms - metabolism
Squamous cell carcinoma
Stem cells
Stromal cells
Tumor Suppressor Protein p53 - metabolism
Tumors
Ultraviolet radiation
Ultraviolet Rays
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0401141101