The basal layer in human squamous tumors harbors more UVA than UVB fingerprint mutations: A role for UVA in human skin carcinogenesis

TLDR

Unrepaired UV‑induced DNA adducts can lead to fixed genomic mutations. The study hypothesizes that many sun‑induced mutagenic changes in the basal layer of human skin arise from UVA wavelengths. Laser capture microdissection was used to analyze basal and suprabasal keratinocytes from squamous cell carcinomas and solar keratosis for UVA and UVB adducts and mutation signatures. UVA‑induced fingerprint mutations and 8‑hydroxy‑2′‑deoxyguanine adducts were predominantly found in the basal layer, whereas UVB‑induced cyclobutane thymine dimers were mainly suprabasal, indicating that UVA contributes significantly to carcinogenesis in skin stem cells and warranting a shift in public health strategies.

Abstract

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.