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Two genetic hits (more or less) to cancer

Abstract

Most cancers have many chromosomal abnormalities, both in number and in structure, whereas some show only a single aberration. In the era before molecular biology, cancer researchers, studying both human and animal cancers, proposed that a small number of events was needed for carcinogenesis. Evidence from the recent molecular era also indicates that cancers can arise from small numbers of events that affect common cell birth and death processes.

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Figure 1: Log–log plots of cancer death rates in males (per 100,000) versus age, showing a linear relationship that is consistent throughout the developed world.
Figure 2: A comparison of karyotypes.
Figure 3: One-hit and two-hit curves for retinoblastoma.
Figure 4: Two-hit tumour formation in both hereditary and nonhereditary retinoblastoma.
Figure 5: A possible five-hit scenario for colorectal cancer, showing the mutational events that correlate with each step in the adenoma–carcinoma sequence.

References

  1. Boveri, T. Zur Frage der Entstehung Maligner Tumoren (Gustav Fischer, Jena); English translation The Origin of Malignant Tumors by Boveri, M. (Williams and Wilkins, Baltimore, 1929, 1914).

    Google Scholar 

  2. von Hansemann, D. Über asymmetrische Zellteilung in Epithelkrebsen und deren biologische Bedeutung. Virchow's Arch. Path. Anat. 119, 299–326 (1890).

    Article  Google Scholar 

  3. Balmain, A. Cancer genetics: from Boveri and Mendel to microarrays. Nature Rev. Cancer 1, 77–80 (2001).

    Article  CAS  Google Scholar 

  4. Tyzzer, E. E. Tumor immunity. J. Cancer Res. 1, 125–156 (1916).

    CAS  Google Scholar 

  5. Muller, H. J. Artificial transmutation of the gene. Science 46, 84–87 (1927).

    Article  Google Scholar 

  6. Muller, H. J. Radiation damage to the genetic material. Sci. Progress 7, 93–165, 481–493 (1951).

    Google Scholar 

  7. Cleaver, J. E. Defective repair replication of DNA in xeroderma pigmentosum. Nature 218, 652–656 (1968).

    Article  CAS  Google Scholar 

  8. Berenblum, I. & Shubik, P. A new, quantitative, approach to the study of the stages of chemical carcinogenesis in the mouse's skin. Br. J. Cancer 1, 383–391 (1947).

    Article  CAS  Google Scholar 

  9. Ames, B. N., Sims, P. & Grover, P. L. Epoxides of carcinogenic polycyclic hydrocarbons are frameshift mutagens. Science 176, 47–49 (1972).

    Article  CAS  Google Scholar 

  10. Armitage, P. & Doll, R. The age distribution of cancer and a multi-stage theory of carcinogenesis. Br. J. Cancer 8, 1–12 (1954).

    Article  CAS  Google Scholar 

  11. Nordling, C. E. A new theory on the cancer-inducing mechanism. Br. J. Cancer 6, 68–72 (1953).

    Article  Google Scholar 

  12. Ashley, D. J. B. The two 'hit' and multiple 'hit' theories of carcinogenesis. Br. J. Cancer 23, 313–328 (1969).

    Article  CAS  Google Scholar 

  13. Ashley, D. J. B. Colonic cancer arising in polyposis coli. J. Med. Genet. 6, 376–378 (1969).

    Article  CAS  Google Scholar 

  14. Ichii, S. et al. Inactivation of both APC alleles in an early stage of colon adenomas in a patient with familial adenomatous polyposis (FAP). Hum. Mol. Genet. 1, 387–390 (1992).

    Article  CAS  Google Scholar 

  15. Nishisho, I. et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253, 665–669 (1991).

    Article  CAS  Google Scholar 

  16. Armitage, P. & Doll, R. A two-stage theory of carcinogenesis in relation to the age distribution of human cancer. Br. J. Cancer 11, 161–169 (1957).

    Article  CAS  Google Scholar 

  17. Moolgavkar, S. H. & Venzon, D. J. Two-event model for carcinogenesis: incidence curves for childhood and adult tumors. Mater. Biosci. 47, 55–77 (1979).

    Article  Google Scholar 

  18. Moolgavkar, S. H. & Knudson, A. G. Mutation and cancer: a model for human carcinogenesis. J. Natl Cancer Inst. 66, 1037–1052 (1981).

    Article  CAS  Google Scholar 

  19. Nowell, P. C. & Hungerford, D. A. A minute chromosome in human chronic granulocytic leukemia. Science 132, 1497 (1960).

    Google Scholar 

  20. Rowley, J. D. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243, 290–293 (1973).

    Article  CAS  Google Scholar 

  21. Stehelin, D., Varmus, H. E., Bishop, J. M. & Vogt, P. K. DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260, 170–173 (1976).

    Article  CAS  Google Scholar 

  22. Shih, C., Shilo, B. Z., Goldfarb, M. P., Dannenberg, A. & Weinberg, R. A. Passage of phenotypes of chemically transformed cells via transfection of DNA and chromatin. Proc. Natl Acad. Sci. USA 76, 5714–5718 (1979).

    Article  CAS  Google Scholar 

  23. Dalla-Favera, R. et al. Human c-MYC onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc. Natl Acad. Sci. USA 79, 7824–7827 (1982).

    Article  CAS  Google Scholar 

  24. Taub, R. et al. Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc. Natl Acad. Sci. USA 79, 7837–7841 (1982).

    Article  CAS  Google Scholar 

  25. Konopka, J. B., Watanabe, S. M., Singer, J. W., Collins, S. J. & Witte, O. N. Cell lines and clinical isolates derived from Ph1-positive chronic myelogenous leukemia patients express c-ABL proteins with a common structural alteration. Proc. Natl Acad. Sci. USA 82, 1810–1814 (1985).

    Article  CAS  Google Scholar 

  26. Shtivelman, E., Lifshitz, B., Gale, R. P. & Canaani, E. Fused transcript of ABL and BCR genes in chronic myelogenous leukaemia. Nature 315, 550–554 (1985).

    Article  CAS  Google Scholar 

  27. Stam, K. et al. Evidence of a new chimeric BCR/c-ABL mRNA in patients with chronic myelocytic leukemia and the Philadelphia chromosome. N. Engl. J. Med. 313, 1429–1433 (1985).

    Article  CAS  Google Scholar 

  28. Skorski, T. et al. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/AKT-dependent pathway. EMBO J. 16, 6151–6161 (1997).

    Article  CAS  Google Scholar 

  29. Druker, B. J. et al. Effects of a selective inhibitor of the ABL tyrosine kinase on the growth of BCR–ABL positive cells. Nature Med. 2, 561–566 (1996).

    Article  CAS  Google Scholar 

  30. Druker, B. J. et al. Activity of a specific inhibitor of the BCR–ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N. Engl. J. Med. 344, 1038–1042 (2001).

    Article  CAS  Google Scholar 

  31. Knudson, A. G. Mutation and cancer: statistical study of retinoblastoma. Proc. Natl Acad. Sci. USA 68, 820–823 (1971).

    Article  Google Scholar 

  32. Hethcote, H. W. & Knudson, A. G. Model for the incidence of embryonal cancers: application to retinoblastoma. Proc. Natl Acad. Sci. USA 75, 2453–2457 (1978).

    Article  CAS  Google Scholar 

  33. Comings, D. E. A general theory of carcinogenesis. Proc. Natl Acad. Sci. USA 70, 3324–3328 (1973).

    Article  CAS  Google Scholar 

  34. Knudson, A. G. Mutation and human cancer. Adv. Cancer Res. 17, 317–352 (1973).

    Article  Google Scholar 

  35. Knudson, A. G. Retinoblastoma: a prototypic hereditary neoplasm. Semin. Oncol. 5, 57–60 (1978).

    PubMed  Google Scholar 

  36. Cavenee, W. K. et al. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305, 779–784 (1983).

    Article  CAS  Google Scholar 

  37. Francke, U. & Kung, F. Sporadic bilateral retinoblastoma and 13q- chromosomal deletion. Med. Pediatr. Oncol. 2, 379–385 (1976).

    Article  CAS  Google Scholar 

  38. Knudson, A. G. Jr,, Meadows, A. T., Nichols, W. W. & Hill, R. Chromosomal deletion and retinoblastoma. N. Engl. J. Med. 295, 1120–1123 (1976).

    Article  Google Scholar 

  39. Friend, S. H. et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323, 643–646 (1986).

    Article  CAS  Google Scholar 

  40. Lane, D. P. & Crawford, L. V. T antigen is bound to a host protein in SV40-transformed cells. Nature 278, 261–263 (1979).

    Article  CAS  Google Scholar 

  41. Linzer, D. I. & Levine, A. J. Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 17, 43–52 (1979).

    Article  CAS  Google Scholar 

  42. Finlay, C. A., Hinds, P. W. & Levine, A. J. The p53 proto-oncogene can act as a suppressor of transformation. Cell 57, 1083–1093 (1989).

    Article  CAS  Google Scholar 

  43. Malkin, D. et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233–1238 (1990).

    Article  CAS  Google Scholar 

  44. Li, F. P. & Fraumeni, J. F. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann. Intern. Med. 71, 747–752 (1969).

    Article  CAS  Google Scholar 

  45. Yonish-Rouach, E. et al. Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature 352, 345–347 (1991).

    Article  CAS  Google Scholar 

  46. Fukasawa, K., Choi, T., Kuriyama, R., Rulong, S. & Vande Woude, G. F. Abnormal centrosome amplification in the absence of p53. Science 271, 1744–1747 (1996).

    Article  CAS  Google Scholar 

  47. Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

    Article  CAS  Google Scholar 

  48. Kikuchi-Yanoshita, R. et al. Genetic changes of both p53 alleles associated with the conversion from colorectal adenoma to early carcinoma in familial adenomatous polyposis and non-familial adenomatous polyposis patients. Cancer Res. 52, 3965–3971 (1992).

    CAS  PubMed  Google Scholar 

  49. Tomlinson, I. & Bodmer, W. Selection, the mutation rate and cancer: ensuring that the tail does not wag the dog. Nature Med. 5, 11–12 (1999).

    Article  CAS  Google Scholar 

  50. Shih, I. M. et al. Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis. Cancer Res. 61, 818–822 (2001).

    CAS  Google Scholar 

  51. Stoler, D. L. et al. The onset and extent of genomic instability in sporadic colorectal tumor progression. Proc. Natl Acad. Sci. USA 96, 15121–15126 (1999).

    Article  CAS  Google Scholar 

  52. Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instabilities in human cancers. Nature 396, 643–649 (1998).

    Article  CAS  Google Scholar 

  53. Loeb, L. A. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res. 51, 3075–3079 (1991).

    CAS  PubMed  Google Scholar 

  54. Bhattacharyya, N. P., Skandalis, A., Ganesh, A., Groden, J. & Meuth, M. Mutator phenotypes in human colorectal carcinoma cell lines. Proc. Natl Acad. Sci. USA 91, 6319–6323 (1994).

    Article  CAS  Google Scholar 

  55. Markowitz, S. et al. Inactivation of the type II TGF-β receptor in colon cancer cells with microsatellite instability. Science 268, 1336–1338 (1995).

    Article  CAS  Google Scholar 

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DATABASES

CancerNet:

breast cancer

Burkitt's lymphoma

chronic myelogenous leukaemia

colorectal carcinomas

osteosarcoma

retinoblastoma

 LocusLink:

ABL

AKT

APC

MLH1

MSH2

MYC

NF1

NF2

HRAS

RB1

TGFBR2

TP53

WT1

 Medscape DrugInfo:

Gleevec

 OMIM:

familial adenomatous polyposis

hereditary non-polyposis colorectal cancer

Li–Fraumeni syndrome

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Knudson, A. Two genetic hits (more or less) to cancer. Nat Rev Cancer 1, 157–162 (2001). https://doi.org/10.1038/35101031

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