Reproducibility and Expression of Skin Biomarkers in Sun-Damaged Skin and Actinic Keratoses

Abstract

Objectives: To explore p53 and proliferating cell nuclear antigen (PCNA) expression and polyamine content as biomarkers in skin cancer chemoprevention trials, we evaluated their expression in early stages of UV-induced squamous cell tumorigenesis. Methods: Biopsies were collected from three groups: 78 subjects with sun damage on forearms, 33 with actinic keratosis (AK) on forearms, and 32 with previous squamous cell carcinoma. Participants with sun damage were randomized to sunscreen or no sunscreen. Results: We found significant differences in p53 and polyamines in forearms from the sun-damaged group (11.5 F 1.2% for p53, 65.5 F 1.9 nmol/g for putrescine, and 187.7 F 3.3 nmol/g for spermidine) compared with the group with sun damage plus AK (20.9 F 2.3% for p53, P = 0.0001; 81.7 F 3.9 nmol/g for putrescine, P = 0.0001; 209.4 F 8.2 nmol/g for spermidine, P < 0.06). PCNA was not different. When lesion histology was considered, there was a stepwise significant increase in p53 in biopsies without characteristics of AK compared with early AK (P = 0.02) and AK (P = 0.0006) and a similar pattern for PCNA with the only significant difference between early AK and AK. There was a stepwise increase in putrescine and spermidine in normal, sun-damaged forearm, forearm from subjects with AK, and the AK lesion itself (P < 0.0001). No significant differences in p53 or polyamines were seen in 3-month biopsies or, as a result of sunscreen use, although PCNA in the sun-damaged group not using sunscreen decreased significantly. Conclusions: p53 expression and polyamines in skin were elevated in early stages of skin tumorigenesis and were not affected by sunscreen, adding validity to their use as biomarkers in skin cancer chemoprevention trials. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1841 -8)

Suberythemal ultraviolet B radiation alters the expression of cell cycle-related proteins in the epidermis of human subjects without leading to photoprotection

“…5,6 TP53 gene mutations are particularly common in skin cancers, [7][8][9] and p53 expression has been suggested as a possible biomarker for actinic keratoses, recognized as the precursor lesions of squamous cell carcinomas. 10 Apoptosis is a physiological process essential for the maintenance of homeostasis by elimination of damaged or mutated cells. Multiple pathways and a variety of environmental, extracellular and internal signals are responsible for the activation and regulation of this process.…”

“…Under various environmental conditions, including UV radiation, the TP53 gene is mutated and loses its regulatory function, thus leading to oncogenic transformation as cells containing mutant p53 have a proliferative advantage over those containing normal p53 5,6 . TP53 gene mutations are particularly common in skin cancers, 7–9 and p53 expression has been suggested as a possible biomarker for actinic keratoses, recognized as the precursor lesions of squamous cell carcinomas 10 …”

New Agents for Prevention of Ultraviolet-Induced Nonmelanoma Skin Cancer

“…Polyamines are known to regulate cellular proliferation, and therefore activation of this enzyme increases the division of mutant cells. 32 During the progression stage, some AK acquire the ability to become invasive NMSC. Molecular and biochemical changes associated with the progression stage include increased angiogenesis, epithelial-mesenchymal transition and the increased activity of myeloid suppressor cells.…”

Risk factors for actinic keratosis in eight European centres: a case-control study

“…UVR acts as an initiator and promoter of carcinogenesis in AK, Bowen disease and SCC, with UVinduced mutations of the tumour suppressor gene TP53 shown to be a reliable biomarker for AK. [24][25][26] Histological, immunohistochemical and molecular studies of AK suggest the same pathogenesis as for Bowen disease and SCC, 27,28 although AK have not been studied in such depth. This hypothesis is reasonable, given that the latter conditions have the same origin and for many authors represent sequential phases of the same process.…”