Genetic Determinants in Carcinogenesis

  • J. C. Barrett
Conference paper
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 128)

Abstract

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).

Keywords

Sarcoma Stein Osteosarcoma Retinoblastoma Neurofibromatosis 

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References

  1. Anisimov VN, Turusov VS (1981) Modifying effect of aging on chemical carcinogenesis. A review. Mech Ageing Dev 15: 399–414PubMedCrossRefGoogle Scholar
  2. 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
  3. 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
  4. Bishop JM (1991) Molecular themes in oncogenesis. Cell 64: 235–248PubMedCrossRefGoogle Scholar
  5. Bols BL, Naaktgeboren JM, Simons JW (1991) Immortalization of Syrian hamster embryo cells is in itself a multistep event. Cancer Res 51: 1177–1184PubMedGoogle Scholar
  6. Boyd J, Barrett JC (1990) Tumor suppressor genes: possible functions in the negative regulation of cell proliferation. Mol Carcinog 3: 325–329PubMedCrossRefGoogle Scholar
  7. Buchkovich K, Duffy LA, Harlow E (1989) The retinoblastoma protein is phosphorylated during specific phases of the cell cycle. Cell 58: 1097–1105PubMedCrossRefGoogle Scholar
  8. Chen P-L, Scully P, Shew J-Y, Wang JYJ, Lee W-H (1989) Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation. Cell 58: 1193–1198PubMedCrossRefGoogle Scholar
  9. Cutler RG, Semsei I (1989) Development, cancer and aging: possible common mechanisms of action and regulation. J Gerontol 44: 25–34PubMedGoogle Scholar
  10. Daniel CW, DeOme KB, Young JT, Blair PB, Faulkin LJ Jr (1968) The in vivo span of normal and preneoplastic mouse mammary glands: a serial transplantation study. Proc Natl Acad Sci USA 61: 53–60PubMedCrossRefGoogle Scholar
  11. DeCaprio JA, Ludlow JW, Lynch D, Furukawa Y, Griffin J, Piwnica Worms H, Huang C-M, Livingston DM (1989) The product of the retinoblastoma susceptibility gene has properties of a cell cycle regulatory element. Cell 58: 1085–1095PubMedCrossRefGoogle Scholar
  12. Ershler WB (1986) Why tumors grow more slowly in old people. J Natl Cancer Inst 77: 837–839PubMedGoogle Scholar
  13. Ershler WB, Stewart JA, Hacker MP, Moore AL, Tindle BH (1984) B16 marine melanoma and aging: slower growth and longer survival in old mice. J Natl Cancer Inst 72: 161–164PubMedGoogle Scholar
  14. Friend SH, Horowitz JM, Gerber MR, Wang X-F, Bogenmann E, Li FP, Weinberg RA (1987) Deletions of a DNA sequence in retinoblastomas and mesenchymal tumors: organization of the sequence and its encoded protein. Proc Natl Acad Sci USA 84: 9059–9063PubMedCrossRefGoogle Scholar
  15. 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
  16. Futreal PA, Barrett JC (1991) Failure of senescent cells to phosphorylate the RB protein. Oncogene 6: 1109–1113PubMedGoogle Scholar
  17. Goldstein S, Murano S, Reis RJS (1990) Werner syndrome: a molecular genetic hypothesis. J Gerontol 45: B3 - B8PubMedGoogle Scholar
  18. Hanawalt PC, Sarasin A (1986) Cancer-prone hereditary diseases with DNA processing abnormalities. Trends Genet 2: 124–129CrossRefGoogle Scholar
  19. Harbour JW, Lai S-L, Whang-Peng J, Gazdar AF, Minna JD, Haye FJ (1988) Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science 241: 353–357PubMedCrossRefGoogle Scholar
  20. Hayflick L (1976) The cell biology of human aging. N Engl J Med 295:1302–1308PubMedCrossRefGoogle Scholar
  21. Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25: 585–621CrossRefGoogle Scholar
  22. Hurlin PJ, Maher VM, McCormick JJ (1989) Malignant transformation of human fibroblasts caused by expression of a transfected T24 HRAS oncogene. Proc Natl Acad Sci USA 86: 187–191PubMedCrossRefGoogle Scholar
  23. 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
  24. Klein CB, Conway K, Wang XW, Bhamra RK, Lin X, Cohen MD, Annab L, Barrett JC, Costa M (1991) Senescence of nickel-transformed cells by a mammalian X chromosome: possible epigenetic control. Science 251: 796–799PubMedCrossRefGoogle Scholar
  25. Koi M, Barrett JC (1986) Loss of tumor-suppressive function during chemically induced neoplastic progression of Syrian hamster embryo cells. Proc Natl Acad Sci USA 83: 5992–5996PubMedCrossRefGoogle Scholar
  26. Lee EY-HP, To H, Shew Y-Y, Bookstein R, Scully P, Lee W-H (1988) Inactivation of the retinoblastoma susceptibility gene in human breast cancers. Science 241: 218–221PubMedCrossRefGoogle Scholar
  27. Lee H-H, Shew J-Y, Hong FD, Shery TW, Domoso LA, Young L-J, Bookstein R, Lee ER-H (1987) The retinoblastoma susceptibility gene encodes a nuclear phosphoprotein associated with DNA binding activity. Nature 329: 642–646PubMedCrossRefGoogle Scholar
  28. 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
  29. 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
  30. Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, Friend SH (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250: 1233–1238PubMedCrossRefGoogle Scholar
  31. McCormick JJ, Maher VIVI (1988) Towards an understanding of the malignant transformation of diploid human fibroblasts. Mutat Res 199: 273–291PubMedCrossRefGoogle Scholar
  32. Mihara K, Cao X-R, Yen A, Chandler S, Driscoll B, Murphree AL, T’Ang A, Fung Y-KY (1989) Cell cycle-dependent regulation of phosphorylation of the human retinoblastoma gene product. Science 246: 1300–1303PubMedCrossRefGoogle Scholar
  33. Ning Y, Weber JL, Killary AM, Ledbetter DH, Smith JR, Pereira-Smith OM (1991) Genetic analysis of indefinite division in human cells: evidence for a cell senescence-related gene(s) on human chromosome 4. Proc Natl Acad Sci USA 88: 5635–5639PubMedCrossRefGoogle Scholar
  34. Pereira-Smith OM, Smith JR (1988) Genetic analysis of indefinite division in human cells: identification of four complementation groups. Proc Natl Acad Sci USA 85: 6043–6046CrossRefGoogle Scholar
  35. Peto R, Roe FJC, Lee PN, Levy L, Clack J (1975) Cancer and ageing in mice and men. Br J Cancer 32: 411–426PubMedCrossRefGoogle Scholar
  36. Rhim JS, Jay G, Arnstein P, Price FM, Sanford KK, Aaronson SA (1985) Neoplastic transformation of human epidermal keratinocytes by AD12–SV40 and Kirsten sarcoma viruses. Science 227: 1250–1252PubMedCrossRefGoogle Scholar
  37. Richter KH, Afshari CA, Annab LA, Burkhart BA, Owen RD, Boyd J, Barrett JC (1991) Downregulation of cdc2 in senescent human and hamster cells. Cancer Res 51: 6010–6013PubMedGoogle Scholar
  38. Sager R (1986) Genetic suppression of tumor formation: A new frontier in cancer research. Cancer Res 46: 1573–1580PubMedGoogle Scholar
  39. 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
  40. Stein GH, Beeson M, Gordon L (1990) Failure to phosphorylate the retinoblastoma gene product in senescent human fibroblasts. Science 249: 666–669PubMedCrossRefGoogle Scholar
  41. Stratton MR, Williams S, Fisher C, Ball A, Westbury G, Gusterson BA, Fletcher CDM, Knight JC, Fung Y-K, Reeves BR, Cooper CS (1989) Structural alterations in the RB1 gene in human soft tissue tumours. Br J Cancer 60: 202–205PubMedCrossRefGoogle Scholar
  42. Sugawara O, Oshimura M, Koi M, Annab L, Barrett JC (1990) Induction of cellular senescence in immortalized cells by human chromosome 1. Science 247: 707–710PubMedCrossRefGoogle Scholar
  43. T’Ang A, Varley JM, Chakraborty S, Murphree AL, Fung Y-KT (1988) Structural rearrangement of the retinoblastoma gene in human breast carcinoma. Science 242: 263–266PubMedCrossRefGoogle Scholar
  44. Tsutsui T, Suzuki N, Maizumi H, Barrett JC (1990) Aneuploidy induction in human fibroblasts: comparison with results in Syrian hamster fibroblasts. Mutat Res 240: 241–249PubMedCrossRefGoogle Scholar
  45. Volk MK, Ershler WB (1991) The influence of immunosenescence on tumor growth and spread; lesions from animal models. Cancer Cells 3: 13–18PubMedGoogle Scholar
  46. Weichselbaum RR, Beckett M, Diamond A (1988) Some retinoblastomas, osteosarcomas, and soft tissue sarcomas may share a common etiology. Proc Natl Acad Sci USA 85: 2106–2109PubMedCrossRefGoogle Scholar
  47. Yamada H, Wake N, Fujimoto S, Barrett JC, Oshimura M (1990) Multiple chromosomes carrying tumor suppressor activity for a uterine endometrial carcinoma cell line identified by microcell mediated chromosome transfer. Oncogene 5: 1141–1147PubMedGoogle Scholar
  48. 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

Copyright information

© Springer-Verlag Berlin · Heidelberg 1993

Authors and Affiliations

  • J. C. Barrett
    • 1
  1. 1.Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health SciencesNational Institutes of HealthUSA

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