Skin tumors oncogenes

The role of depurinating adducts and apurinic sites in the PAH-induced cancer process is controversial and has yet to be fully elucidated. There are lines of evidence that both support and refute this theory. In support of this theory, the levels of depurinating adducts of B[a]P correlated with mutations in the H-ras oncogene in DNA isolated from mouse skin papillomas initiated by this compound (Chakravarti et al. 1995). It is well known that the initiation of skin tumors in mice is associated with the formation of mutations in the H-ras gene [reviewed by Ross and Nesnow (1999)]. DB[a,/]P treatment of mouse skin forms papillomas which contain the H-ras codon 61 (CAA to CTA) mutation. These same mutations were induced in early preneoplastic skin within one day after DB[a,/]P treatment and appear to be related to DB[a,/]P-Ade-depurinating adducts. Studies have shown that apurinic... 

Figure 6.51 Scheme showing the initiation and promotion of skin papillomas and carcinomas after treatment with DMBA and promotion with TPA (Fig. 53). The initiation converts (mutation) proto-oncogene ras to oncogene and promotion stimulates growth and division, forming a papilloma. Further exposure to initiator DMBA, alters (mutation) tumor suppressor gene p53 which collaborates with ras and causes carcinoma formation. See text for full explanation. Abbreviation DMBA, dimethylbenzanthracene. Source From Ref. 15.

Although tumor induction has mostly been documented in patients treated for cancer, long-term cyclophosphamide treatment for non-neoplastic conditions can also increase the incidence of certain neoplasms. Whether this oncogenic effect is a consequence of drug-induced chromosomal aberrations rather than immunosuppression is unclear. An increased incidence of bladder cancers, skin cancers, and myeloproliferative disorders was found in a 20-year follow-up study of 119 patients with rheumatoid arthritis, and a high dose of cyclophosphamide (mean total dose of 80 g) was the main susceptibihty factor (47). 

In order for most oncogenic mutations to induce cancer, they must occur in dividing cells so that the mutation is passed on to many progeny cells. When such mutations occur in nondividing cells (e.g., neurons and muscle cells), they generally do not induce cancer, which is why tumors of muscle and nerve cells are rare in adults. Nonetheless, cancer can occur in tissues composed mainly of nondividing differentiated cells such as erythrocytes and most white blood cells, absorptive cells that line the small Intestine, and keratinized cells that form the skin. The cells that Initiate the tumors are not the differentiated cells, but rather their precursor cells. Fully differentiated cells usually do not divide. As they die or wear out, they are continually replaced by proliferation and differentiation of stem cells, and these cells are capable of transforming Into tumor cells. 

Pyrimidine dimers occur frequently in the skin. Usually repair mechanisms correct this damage, and cancer rarely occurs. However, in individuals with xeroderma pigmentosum, cancers are extremely common. These individuals have defects in their DNA repair systems. The first defect to be identified was a deficiency of the endonuclease involved in removal of pyrimidine dimers from DNA. Because of the inability to repair DNA, the frequency of mutation increases. A cancer develops once proto-oncogenes or tumor suppressor genes mutate. By scrupulously avoiding light, these individuals can reduce the number of skin cancers that develop. 

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