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Activated ras genes occur in human actinic keratoses, premalignant precursors to squamous cell carcinomas
J M Spencer1, S M Kahn, W Jiang
1Department of Dermatology, Columbia University, New York, NY, USA.
Unlabelled:
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 ras 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-ras 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.
Insights
Activated ras genes are found in early skin cancer precursors, actinic keratoses, and squamous cell carcinomas. This suggests ras gene activation is an early event in skin tumor development, possibly due to UV damage repair issues.
Area of Science:
- Oncology
- Molecular Biology
- Dermatology
Background:
- The clonal theory of cancer posits tumors arise from a single initiated cell accumulating genetic/epigenetic lesions.
- Mammalian ras genes, crucial for mitogenic signaling, drive deregulated growth when activated.
- Activated ras genes are implicated in skin tumor development, potentially as an early event.
Purpose of the Study:
- To investigate the incidence of activated ras genes in actinic keratoses, premalignant precursors to squamous cell carcinomas.
- To understand the role of activated ras genes in the early stages of squamous cell carcinoma development.
Main Methods:
- Utilized a nonradioactive polymerase chain reaction-based method.
- Examined 19 actinic keratoses and 33 squamous cell carcinomas for activated ras genes.
Main Results:
- Ras gene mutations were detected in 16% of actinic keratoses and 12% of squamous cell carcinomas.
- Mutations occurred at specific codons in K-ras and H-ras genes.
- All positive samples originated from sun-exposed skin areas.
Conclusions:
- Activated ras genes play significant roles in the early development of squamous cell carcinoma.
- Aberrant repair of UV-induced pyrimidine dimers is a probable cause for ras gene activation in skin tumors.