Skip to main content
British Journal of Cancer logoLink to British Journal of Cancer
. 1989 May;59(5):661–666. doi: 10.1038/bjc.1989.137

The ninth Gordon Hamilton-Fairley memorial lecture. Hereditary cancers: clues to mechanisms of carcinogenesis.

A G Knudson Jr 1
PMCID: PMC2247235  PMID: 2660894

Abstract

The study of hereditary cancer in humans, notably retinoblastoma, has identified a category of cancer genes that is different from that of the oncogenes. Whereas the latter group of genes exerts its effect through expression, the former does so as a result of failure of normal expression. Primary oncogene abnormality seems to play a crucial initiating role in certain neoplasms, particularly leukaemias, lymphomas and some sarcomas. In contrast, anti-oncogenes (tumour suppressor genes) appear to be important in the initiation of several solid tumours of children, as well as some common carcinomas of adults. Both classes are apparently involved in tumour progression and metastasis. Virtually every kind of cancer can occur in hereditary form, so the role of anti-oncogenes in the origin of human cancers may be considerable. The prototypic anti-oncogene has been that for retinoblastoma. For this tumour the recessive mechanism has been demonstrated by molecular means, and the gene has been cloned. The possibility has been suggested that gene (or gene product) replacement therapy could be accomplished.

Full text

PDF

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ARMITAGE P., DOLL R. The age distribution of cancer and a multi-stage theory of carcinogenesis. Br J Cancer. 1954 Mar;8(1):1–12. doi: 10.1038/bjc.1954.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ali I. U., Lidereau R., Theillet C., Callahan R. Reduction to homozygosity of genes on chromosome 11 in human breast neoplasia. Science. 1987 Oct 9;238(4824):185–188. doi: 10.1126/science.3659909. [DOI] [PubMed] [Google Scholar]
  3. Arinami T., Kondo I., Hamaguchi H., Nakajima S. Multifocal meningiomas in a patient with a constitutional ring chromosome 22. J Med Genet. 1986 Apr;23(2):178–180. doi: 10.1136/jmg.23.2.178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Benedict W. F., Murphree A. L., Banerjee A., Spina C. A., Sparkes M. C., Sparkes R. S. Patient with 13 chromosome deletion: evidence that the retinoblastoma gene is a recessive cancer gene. Science. 1983 Feb 25;219(4587):973–975. doi: 10.1126/science.6336308. [DOI] [PubMed] [Google Scholar]
  5. Bodmer W. F., Bailey C. J., Bodmer J., Bussey H. J., Ellis A., Gorman P., Lucibello F. C., Murday V. A., Rider S. H., Scambler P. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature. 1987 Aug 13;328(6131):614–616. doi: 10.1038/328614a0. [DOI] [PubMed] [Google Scholar]
  6. Bookstein R., Lee E. Y., To H., Young L. J., Sery T. W., Hayes R. C., Friedmann T., Lee W. H. Human retinoblastoma susceptibility gene: genomic organization and analysis of heterozygous intragenic deletion mutants. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2210–2214. doi: 10.1073/pnas.85.7.2210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cavenee W. K., Dryja T. P., Phillips R. A., Benedict W. F., Godbout R., Gallie B. L., Murphree A. L., Strong L. C., White R. L. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. 1983 Oct 27-Nov 2Nature. 305(5937):779–784. doi: 10.1038/305779a0. [DOI] [PubMed] [Google Scholar]
  8. Cohen A. J., Li F. P., Berg S., Marchetto D. J., Tsai S., Jacobs S. C., Brown R. S. Hereditary renal-cell carcinoma associated with a chromosomal translocation. N Engl J Med. 1979 Sep 13;301(11):592–595. doi: 10.1056/NEJM197909133011107. [DOI] [PubMed] [Google Scholar]
  9. Dryja T. P., Rapaport J. M., Joyce J. M., Petersen R. A. Molecular detection of deletions involving band q14 of chromosome 13 in retinoblastomas. Proc Natl Acad Sci U S A. 1986 Oct;83(19):7391–7394. doi: 10.1073/pnas.83.19.7391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dunn J. M., Phillips R. A., Becker A. J., Gallie B. L. Identification of germline and somatic mutations affecting the retinoblastoma gene. Science. 1988 Sep 30;241(4874):1797–1800. doi: 10.1126/science.3175621. [DOI] [PubMed] [Google Scholar]
  11. Erisman M. D., Rothberg P. G., Diehl R. E., Morse C. C., Spandorfer J. M., Astrin S. M. Deregulation of c-myc gene expression in human colon carcinoma is not accompanied by amplification or rearrangement of the gene. Mol Cell Biol. 1985 Aug;5(8):1969–1976. doi: 10.1128/mcb.5.8.1969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fearon E. R., Vogelstein B., Feinberg A. P. Somatic deletion and duplication of genes on chromosome 11 in Wilms' tumours. Nature. 1984 May 10;309(5964):176–178. doi: 10.1038/309176a0. [DOI] [PubMed] [Google Scholar]
  13. Francke U., Holmes L. B., Atkins L., Riccardi V. M. Aniridia-Wilms' tumor association: evidence for specific deletion of 11p13. Cytogenet Cell Genet. 1979;24(3):185–192. doi: 10.1159/000131375. [DOI] [PubMed] [Google Scholar]
  14. Francke U., Kung F. Sporadic bilateral retinoblastoma and 13q- chromosomal deletion. Med Pediatr Oncol. 1976;2(4):379–385. doi: 10.1002/mpo.2950020404. [DOI] [PubMed] [Google Scholar]
  15. Friend S. H., Bernards R., Rogelj S., Weinberg R. A., Rapaport J. M., Albert D. M., Dryja T. P. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986 Oct 16;323(6089):643–646. doi: 10.1038/323643a0. [DOI] [PubMed] [Google Scholar]
  16. Friend S. H., Horowitz J. M., Gerber M. R., Wang X. F., Bogenmann E., Li F. P., Weinberg R. A. Deletions of a DNA sequence in retinoblastomas and mesenchymal tumors: organization of the sequence and its encoded protein. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9059–9063. doi: 10.1073/pnas.84.24.9059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fung Y. K., Murphree A. L., T'Ang A., Qian J., Hinrichs S. H., Benedict W. F. Structural evidence for the authenticity of the human retinoblastoma gene. Science. 1987 Jun 26;236(4809):1657–1661. doi: 10.1126/science.2885916. [DOI] [PubMed] [Google Scholar]
  18. Godbout R., Dryja T. P., Squire J., Gallie B. L., Phillips R. A. Somatic inactivation of genes on chromosome 13 is a common event in retinoblastoma. Nature. 1983 Aug 4;304(5925):451–453. doi: 10.1038/304451a0. [DOI] [PubMed] [Google Scholar]
  19. Harbour J. W., Lai S. L., Whang-Peng J., Gazdar A. F., Minna J. D., Kaye F. J. Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science. 1988 Jul 15;241(4863):353–357. doi: 10.1126/science.2838909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Herrera L., Kakati S., Gibas L., Pietrzak E., Sandberg A. A. Gardner syndrome in a man with an interstitial deletion of 5q. Am J Med Genet. 1986 Nov;25(3):473–476. doi: 10.1002/ajmg.1320250309. [DOI] [PubMed] [Google Scholar]
  21. Hethcote H. W., Knudson A. G., Jr Model for the incidence of embryonal cancers: application to retinoblastoma. Proc Natl Acad Sci U S A. 1978 May;75(5):2453–2457. doi: 10.1073/pnas.75.5.2453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Huang H. J., Yee J. K., Shew J. Y., Chen P. L., Bookstein R., Friedmann T., Lee E. Y., Lee W. H. Suppression of the neoplastic phenotype by replacement of the RB gene in human cancer cells. Science. 1988 Dec 16;242(4885):1563–1566. doi: 10.1126/science.3201247. [DOI] [PubMed] [Google Scholar]
  23. Knudson A. G., Jr Hereditary cancer, oncogenes, and antioncogenes. Cancer Res. 1985 Apr;45(4):1437–1443. [PubMed] [Google Scholar]
  24. Knudson A. G., Jr, Meadows A. T., Nichols W. W., Hill R. Chromosomal deletion and retinoblastoma. N Engl J Med. 1976 Nov 11;295(20):1120–1123. doi: 10.1056/NEJM197611112952007. [DOI] [PubMed] [Google Scholar]
  25. Knudson A. G., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. doi: 10.1073/pnas.68.4.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Knudson A. G., Jr Retinoblastoma: a prototypic hereditary neoplasm. Semin Oncol. 1978 Mar;5(1):57–60. [PubMed] [Google Scholar]
  27. Knudson A. G., Jr, Strong L. C. Mutation and cancer: a model for Wilms' tumor of the kidney. J Natl Cancer Inst. 1972 Feb;48(2):313–324. [PubMed] [Google Scholar]
  28. Kok K., Osinga J., Carritt B., Davis M. B., van der Hout A. H., van der Veen A. Y., Landsvater R. M., de Leij L. F., Berendsen H. H., Postmus P. E. Deletion of a DNA sequence at the chromosomal region 3p21 in all major types of lung cancer. Nature. 1987 Dec 10;330(6148):578–581. doi: 10.1038/330578a0. [DOI] [PubMed] [Google Scholar]
  29. Koufos A., Hansen M. F., Lampkin B. C., Workman M. L., Copeland N. G., Jenkins N. A., Cavenee W. K. Loss of alleles at loci on human chromosome 11 during genesis of Wilms' tumour. Nature. 1984 May 10;309(5964):170–172. doi: 10.1038/309170a0. [DOI] [PubMed] [Google Scholar]
  30. Kovacs G., Erlandsson R., Boldog F., Ingvarsson S., Müller-Brechlin R., Klein G., Sümegi J. Consistent chromosome 3p deletion and loss of heterozygosity in renal cell carcinoma. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1571–1575. doi: 10.1073/pnas.85.5.1571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Law D. J., Olschwang S., Monpezat J. P., Lefrançois D., Jagelman D., Petrelli N. J., Thomas G., Feinberg A. P. Concerted nonsyntenic allelic loss in human colorectal carcinoma. Science. 1988 Aug 19;241(4868):961–965. doi: 10.1126/science.2841761. [DOI] [PubMed] [Google Scholar]
  32. Lee E. Y., To H., Shew J. Y., Bookstein R., Scully P., Lee W. H. Inactivation of the retinoblastoma susceptibility gene in human breast cancers. Science. 1988 Jul 8;241(4862):218–221. doi: 10.1126/science.3388033. [DOI] [PubMed] [Google Scholar]
  33. Lee W. H., Bookstein R., Hong F., Young L. J., Shew J. Y., Lee E. Y. Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science. 1987 Mar 13;235(4794):1394–1399. doi: 10.1126/science.3823889. [DOI] [PubMed] [Google Scholar]
  34. Lee W. H., Shew J. Y., Hong F. D., Sery T. W., Donoso L. A., Young L. J., Bookstein R., Lee E. Y. The retinoblastoma susceptibility gene encodes a nuclear phosphoprotein associated with DNA binding activity. Nature. 1987 Oct 15;329(6140):642–645. doi: 10.1038/329642a0. [DOI] [PubMed] [Google Scholar]
  35. Leppert M., Dobbs M., Scambler P., O'Connell P., Nakamura Y., Stauffer D., Woodward S., Burt R., Hughes J., Gardner E. The gene for familial polyposis coli maps to the long arm of chromosome 5. Science. 1987 Dec 4;238(4832):1411–1413. doi: 10.1126/science.3479843. [DOI] [PubMed] [Google Scholar]
  36. Li F. P., Fraumen J. F., Jr Letter: Familial breast cancer, soft-tissue sarcomas, and other neoplasms. Ann Intern Med. 1975 Dec;83(6):833–834. doi: 10.7326/0003-4819-83-6-833_2. [DOI] [PubMed] [Google Scholar]
  37. Lundberg C., Skoog L., Cavenee W. K., Nordenskjöld M. Loss of heterozygosity in human ductal breast tumors indicates a recessive mutation on chromosome 13. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2372–2376. doi: 10.1073/pnas.84.8.2372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. MILLER R. W., FRAUMENI J. F., Jr, MANNING M. D. ASSOCIATION OF WILMS'S TUMOR WITH ANIRIDIA, HEMIHYPERTROPHY AND OTHER CONGENITAL MALFORMATIONS. N Engl J Med. 1964 Apr 30;270:922–927. doi: 10.1056/NEJM196404302701802. [DOI] [PubMed] [Google Scholar]
  39. Mathew C. G., Chin K. S., Easton D. F., Thorpe K., Carter C., Liou G. I., Fong S. L., Bridges C. D., Haak H., Kruseman A. C. A linked genetic marker for multiple endocrine neoplasia type 2A on chromosome 10. Nature. 1987 Aug 6;328(6130):527–528. doi: 10.1038/328527a0. [DOI] [PubMed] [Google Scholar]
  40. Meese E., Blin N., Zang K. D. Loss of heterozygosity and the origin of meningioma. Hum Genet. 1987 Dec;77(4):349–351. doi: 10.1007/BF00291425. [DOI] [PubMed] [Google Scholar]
  41. Moolgavkar S. H., Knudson A. G., Jr Mutation and cancer: a model for human carcinogenesis. J Natl Cancer Inst. 1981 Jun;66(6):1037–1052. doi: 10.1093/jnci/66.6.1037. [DOI] [PubMed] [Google Scholar]
  42. Naylor S. L., Johnson B. E., Minna J. D., Sakaguchi A. Y. Loss of heterozygosity of chromosome 3p markers in small-cell lung cancer. Nature. 1987 Oct 1;329(6138):451–454. doi: 10.1038/329451a0. [DOI] [PubMed] [Google Scholar]
  43. Orkin S. H., Goldman D. S., Sallan S. E. Development of homozygosity for chromosome 11p markers in Wilms' tumour. Nature. 1984 May 10;309(5964):172–174. doi: 10.1038/309172a0. [DOI] [PubMed] [Google Scholar]
  44. Reeve A. E., Housiaux P. J., Gardner R. J., Chewings W. E., Grindley R. M., Millow L. J. Loss of a Harvey ras allele in sporadic Wilms' tumour. Nature. 1984 May 10;309(5964):174–176. doi: 10.1038/309174a0. [DOI] [PubMed] [Google Scholar]
  45. Rouleau G. A., Wertelecki W., Haines J. L., Hobbs W. J., Trofatter J. A., Seizinger B. R., Martuza R. L., Superneau D. W., Conneally P. M., Gusella J. F. Genetic linkage of bilateral acoustic neurofibromatosis to a DNA marker on chromosome 22. Nature. 1987 Sep 17;329(6136):246–248. doi: 10.1038/329246a0. [DOI] [PubMed] [Google Scholar]
  46. Scrable H. J., Witte D. P., Lampkin B. C., Cavenee W. K. Chromosomal localization of the human rhabdomyosarcoma locus by mitotic recombination mapping. Nature. 1987 Oct 15;329(6140):645–647. doi: 10.1038/329645a0. [DOI] [PubMed] [Google Scholar]
  47. Seizinger B. R., Martuza R. L., Gusella J. F. Loss of genes on chromosome 22 in tumorigenesis of human acoustic neuroma. Nature. 1986 Aug 14;322(6080):644–647. doi: 10.1038/322644a0. [DOI] [PubMed] [Google Scholar]
  48. Seizinger B. R., Rouleau G. A., Ozelius L. J., Lane A. H., Farmer G. E., Lamiell J. M., Haines J., Yuen J. W., Collins D., Majoor-Krakauer D. Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature. 1988 Mar 17;332(6161):268–269. doi: 10.1038/332268a0. [DOI] [PubMed] [Google Scholar]
  49. Seizinger B. R., de la Monte S., Atkins L., Gusella J. F., Martuza R. L. Molecular genetic approach to human meningioma: loss of genes on chromosome 22. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5419–5423. doi: 10.1073/pnas.84.15.5419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Simpson N. E., Kidd K. K., Goodfellow P. J., McDermid H., Myers S., Kidd J. R., Jackson C. E., Duncan A. M., Farrer L. A., Brasch K. Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage. Nature. 1987 Aug 6;328(6130):528–530. doi: 10.1038/328528a0. [DOI] [PubMed] [Google Scholar]
  51. Solomon E., Voss R., Hall V., Bodmer W. F., Jass J. R., Jeffreys A. J., Lucibello F. C., Patel I., Rider S. H. Chromosome 5 allele loss in human colorectal carcinomas. Nature. 1987 Aug 13;328(6131):616–619. doi: 10.1038/328616a0. [DOI] [PubMed] [Google Scholar]
  52. Sparkes R. S., Murphree A. L., Lingua R. W., Sparkes M. C., Field L. L., Funderburk S. J., Benedict W. F. Gene for hereditary retinoblastoma assigned to human chromosome 13 by linkage to esterase D. Science. 1983 Feb 25;219(4587):971–973. doi: 10.1126/science.6823558. [DOI] [PubMed] [Google Scholar]
  53. Sparkes R. S., Sparkes M. C., Wilson M. G., Towner J. W., Benedict W., Murphree A. L., Yunis J. J. Regional assignment of genes for human esterase D and retinoblastoma to chromosome band 13q14. Science. 1980 May 30;208(4447):1042–1044. doi: 10.1126/science.7375916. [DOI] [PubMed] [Google Scholar]
  54. Turleau C., de Grouchy J., Chavin-Colin F., Martelli H., Voyer M., Charlas R. Trisomy 11p15 and Beckwith-Wiedemann syndrome. A report of two cases. Hum Genet. 1984;67(2):219–221. doi: 10.1007/BF00273006. [DOI] [PubMed] [Google Scholar]
  55. Vogelstein B., Fearon E. R., Hamilton S. R., Kern S. E., Preisinger A. C., Leppert M., Nakamura Y., White R., Smits A. M., Bos J. L. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988 Sep 1;319(9):525–532. doi: 10.1056/NEJM198809013190901. [DOI] [PubMed] [Google Scholar]
  56. Wang N., Perkins K. L. Involvement of band 3p14 in t(3;8) hereditary renal carcinoma. Cancer Genet Cytogenet. 1984 Apr;11(4):479–481. doi: 10.1016/0165-4608(84)90028-1. [DOI] [PubMed] [Google Scholar]
  57. Waziri M., Patil S. R., Hanson J. W., Bartley J. A. Abnormality of chromosome 11 in patients with features of Beckwith-Wiedemann syndrome. J Pediatr. 1983 Jun;102(6):873–876. doi: 10.1016/s0022-3476(83)80014-6. [DOI] [PubMed] [Google Scholar]
  58. Weichselbaum R. R., Beckett M., Diamond A. Some retinoblastomas, osteosarcomas, and soft tissue sarcomas may share a common etiology. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2106–2109. doi: 10.1073/pnas.85.7.2106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Weissman B. E., Saxon P. J., Pasquale S. R., Jones G. R., Geiser A. G., Stanbridge E. J. Introduction of a normal human chromosome 11 into a Wilms' tumor cell line controls its tumorigenic expression. Science. 1987 Apr 10;236(4798):175–180. doi: 10.1126/science.3031816. [DOI] [PubMed] [Google Scholar]
  60. Yokota J., Wada M., Shimosato Y., Terada M., Sugimura T. Loss of heterozygosity on chromosomes 3, 13, and 17 in small-cell carcinoma and on chromosome 3 in adenocarcinoma of the lung. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9252–9256. doi: 10.1073/pnas.84.24.9252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Yunis J. J., Ramsay N. Retinoblastoma and subband deletion of chromosome 13. Am J Dis Child. 1978 Feb;132(2):161–163. doi: 10.1001/archpedi.1978.02120270059012. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES