ACTIVATED RAS GENES OCCUR IN HUMAN ACTINIC KERATOSES, PREMALIGNANT PRECURSORS TO SQUAMOUS-CELL CARCINOMAS

Background/Design: The clonal theory of cancer predicts that transformed cells within a given tumor are derived from a single initiated precursor. Advancement of this precursor through various stages of tumor development occurs with the further accumulation of selective genetic and epigenetic lesions. Mammalian pas genes are important constituents of mitogenic signaling pathways, and when activated, they contribute to deregulated cellular growth. Activated ras genes play important roles in the development of certain skin tumors. Studies on a number of animal tumor model systems have shown that ras gene activation can be an early and perhaps initial event in the development of skin tumors. Activated ras genes are also found in a significant percentage of somatic human squamous cell carcinomas. To gain retrospective insight into the stages at which activated ras genes contribute to squamous cell carcinoma development, we investigated their incidence in actinic keratoses, premalignant precursors to squamous cell carcinomas. Using a nonradioactive polymerase chain reaction-based method developed in our laboratory, we examined a panel of 19 actinic keratoses and 33 squamous cell carcinomas for activated ras genes. Results: DNA analysis revealed ras gene mutations in three (16%) of 19 actinic keratoses and in four(12%) of 33 squamous cell carcinomas. Activating mutations occurred at codon 12 of the K-vas gene, and codons 12, 13, and 61 of the H-ras gene. All positive actinic keratoses and squamous cell carcinomas occurred in sun-exposed regions. Conclusions: Activated ras genes can play important roles during early stages of squamous cell carcinoma development. Aberrant repair of UV-induced pyrimidine dimers is a likely cause of this activation.