The Nature of Suppressor Genes

This approach is based on the discovery that carcinogens cause specific mutations in tumors. The unique pattern in UV-induced skin cancers has been identified in the p53-tumor-suppressor gene (Brash et al. 1991 Reid et al. 1992 Somers et al. 1992 Moles et al. 1993 Ziegler et al. 1993 Nakazawa et al. 1994), a key gene which is mutated in more than 50% of all tumors (Greenblatt et al. 1994 HoUstein et al. 1991, 1996). The specific mutations can then be used as a molecular marker for UV-induced skin cancer. We hypothesize that such an indicator can also be found for tar-induced (one example of chemically-induced) SCC skin tumors, which can be differentiated from the genetic marker for UV-induced skin tumors. This proposed study will produce a clearer picture as to the exact nature of occupational skin cancer caused by tar. In addition, it will provide further evidence as to the use of molecular epidemiology in cancer risk assessment. 

Letzel S, Drexler H, Lehnert G (1992) Teer-induzierte Praekan-zerosen und Malignome der Haut bei Beschaeftigten einer Teer-Raffinerie. Dermatosen 40 94-101 Levine AJ, Momand J, Finlay CA (1991) The p53 tumour suppressor gene. Nature 351 453-456 Millard LG (1986) Multiple pigmented papular basal cell carcinomas a new pattern of industrial tar induced skin tumours. Br J Ind Med 43 143-136... 

Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, Latif F, Liu S, Chen F, Duh F-M, Lubensky I, Duan DR, Florence C, Pozzatti R, Walther MM, Bander NH, Grossman HB, Brauch H, Pomer S, Brooks JD, Isaacs WB, Lerman MI, Zbar B, Linehan WM. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nature Genet 1994 7 85-90. 

Duan DR, Humphrey JS, Chen DY, Weng Y, Sukegawa J, Lee S, Gnarra JR, Linehan WM, Klausner RD. Characterization of the VHL tumor suppressor gene product localization, complex formation, and the effect of natural inactivating mutations. Proc Natl Acad Sci USA 1995 92 6459-6463. 

Suppressor tRNAs constitute an experimentally induced variation in the genetic code to allow the reading of what are usually termination codons, much like the naturally occurring code variations described in Box 27-2. Nonsense suppression does not completely disrupt normal information transfer in a cell, because the cell usually has several copies of each tRNA gene some of these duplicate genes are weakly expressed and account for only a minor part of the cellular pool of a particular tRNA. Suppressor mutations usually involve a minor tRNA, leaving the major tRNA to read its codon normally. 

Individuals of the same species may differ significantly in their susceptibilities to various toxic agents. These differences are often genetic in nature. For example, some individuals lack tumor suppressor genes that other individuals possess and are thus more likely to develop some kinds of cancers, some of which are initiated by carcinogens. With increased knowledge of the human genome, these kinds of susceptibilities may become more apparent and appropriate preventive measures may be applied in some cases. 

---