Genetic Determinants in Carcinogenesis
There are three types of risk factors that determine whether an individual will develop cancer — environmental exposures, intrinsic susceptibility, and age/time. It is important, therefore, to understand the genetic determinants underlying these risk factors. The critical target genes for environmental factors are, in part, known and include protooncogenes and tumor suppressor genes (Boyd and Barrett 1990; Bishop 1991). These are discussed further by Balmain, Bowden, and others in this volume. The genetic determinants for intrinsic susceptibility to cancer are of two types. On the one hand, genetic variations exist in genes that influence the impact of environmental agents on an individual, such as genes that control carcinogen metabolism or repair of carcinogenic damage (Hanawalt and Sarasin 1986; Lehmann and Dean 1990). On the other hand, individuals may inherit germ line mutations in genes that are directly involved in the neoplastic conversion of normal cells (Malkin et al. 1990). For example, inherited mutations in tumor suppressor genes can increase the risk of specific cancers. The magnitude of this increased risk can vary greatly depending on the number of additional steps required for the genesis of the tumor. For example, mutations in the rb gene increase the relative risk for retinoblastoma by 105-fold whereas the same mutation, increases the risk for lung cancer by only 10-fold (A. Knudson, personal communication).
KeywordsSarcoma Stein Osteosarcoma Retinoblastoma Neurofibromatosis
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- Barrett JC (1987) Relationship between mutagenesis and carcinogenesis. In: Barrett JC (ed) Mechanisms of environmental carcinogenesis, vol I. CRC, Boca Raton, pp 129–142Google Scholar
- Barrett JC, Fletcher WF (1987) Cellular and molecular mechanisms of multistep carcinogenesis in cell culture models. In: Barrett JC (ed) Mechanisms of environmental carcinogenesis: multistep models of carcinogenesis, vol II. CRC, Boca Raton, pp 73–116Google Scholar
- Furukawa Y, DeCaprio JA, Freedman A, Kanakura Y, Makamura M, Ernst TJ, Livingston DM, Griffin JD (1990) Expression and state of phosphorylation of the retinoblastoma susceptibility gene product in cycling and noncycling human hematopoietic cells. Proc Natl Acad Sci USA 87: 2770–2774PubMedCrossRefGoogle Scholar
- Kaldor JM, Day NE (1987) Interpretation of epidemiological studies on the context of the multistage model of carcinogenesis. In: Barrett JC (ed) Mechanisms of environmental carcinogenesis, vol II. CRC, Boca Raton, pp 21–57Google Scholar
- Lehmann AR, Dean SW (1990) Cancer-prone human disorders with defects in DNA repair. In: Cooper CS, Grover PL (eds) Chemical carcinogenesis and mutagenesis II. Springer, Berlin Heidelberg New York, pp 71–101 (Handbook of experimental pharmacology, vol 94 )Google Scholar
- Macieira-Coelho A (1988) Biology of normal proliferating cells in vitro. Relevance for in vivo aging. In: von Hang HP (ed) Interdisciplinary topics in gerontology, vol 23. Karger, BaselGoogle Scholar
- Salk D, Fujiwara Y, Martin GM (1985) Werner’s symdrome and human aging. Plenum, New York (Advances in experimental medicine and biology, vol 190 )Google Scholar
- Zu H-J, Hu-S-X, Hashimoto T, Takahashi R, Benedict WF (1989) The retinoblastoma susceptibility gene product: a characteristic pattern in normal and abnormal expression in malignant cells. Oncogene 4: 807–812Google Scholar