Hereditary cancer: Two hits revisited

  • Alfred G. Knudson


According to a “two-hit” model, dominantly inherited predisposition to cancer entails a germline mutation, while tumorigenesis requires a second, somatic, mutation. Non-hereditary cancer of the same type requires the same two hits, but both are somatic. The original tumor used in this model, retinoblastoma, involves mutation or loss of both copies of theRB1 tumor-suppressor gene in both hereditary and non-hereditary forms. In fact, most dominantly inherited cancers show this relationship. New questions have arisen, however. When a tumor-suppressor gene is ubiquitously expressed, why is there any specificity of tumor predilection? In some instances, it is clear that two hits produce only a benign precursor lesion and that other genetic events are necessary. As the number of necessary events increases, the impact of the germline mutation diminishes. The number of events is least for embryonal tumors, and relatively small for certain sarcomas. Stem-cell proliferation evidently plays a key role early in carcinogenesis. In some tissues it is physiological, as in embryonic development and in certain tissues in adolescence. In adult renewal tissues, the sites of the common carcinomas, mutation may be necessary to impair the control of switching between renewal and replicative cell divisions; theAPC gene may be the target of such a mutation.

Key words

Heredity Somatic mutations Suppressor genes 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Benedict WF, Murphree AI, Banerjee A, Spina CA, Sparkes MD, Sparkes RS (1983) Patient with 13 chromosome deletion: evidence that the retinoblastoma gene is a recessive cancer gene. Science 219:973–975PubMedGoogle Scholar
  2. Bronner CE, Baker SM, Morrison PT, Warren G, Smith LG, Lescoe MK, Kane M, Earabino C, Lipford J, Lindblom A, Tannergard P, Bollag RJ, Godwin AR, Ward DC, Nordenskjold M, Fishel R, Kolodner R, Liskay RM (1994) Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary nonpolyposis colon cancer. Nature 368:258–261PubMedGoogle Scholar
  3. Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH, Jones C, Housman DE (1990) Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 60:509–520PubMedGoogle Scholar
  4. Cavenee WK, Dryja TP, Phillips RA, Benedict WF, Godbout R, Gallie BL, Murphree AL, Strong LC, White RL (1983) Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305:779–784PubMedGoogle Scholar
  5. Comings DE (1973) A general theory of carcinogenesis. Proc Natl Acad Sci USA 70:3324–3328PubMedGoogle Scholar
  6. Diller L, Kassel J, Nelson CE, Gryka MA, Litwak G, Gebhardt M, Bressac B, Ozturk M, Baker SJ, Vogelstein B, Friend SH (1990) p53 functions as a cell cycle control protein in osteosarcomas. Mol Cell Biol 10:5772–5781PubMedGoogle Scholar
  7. Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P, Wells SA (1993) Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 2:851PubMedGoogle Scholar
  8. Draper GJ, Sanders BM, Kingston JE (1986) Second primary neoplasms in patients with retinoblastoma. Br J Cancer 53:661–671PubMedGoogle Scholar
  9. Ekbom A, Helmick C, Zack M, Adami H-O (1990) Ulcerative colitis and colorectal cancer: a population-based study. N Engl J Med 323:1228–1233PubMedGoogle Scholar
  10. Fearon ER, Vogelstein B (1990) A genetic model of colorectal tumorigenesis. Cell 61:759–767PubMedGoogle Scholar
  11. Fearon ER, Vogelstein B, Feinberg AP (1984) Somatic deletion and duplication of genes on chromosome 11 in Wilms' tumours. Nature 309:176–178PubMedGoogle Scholar
  12. Fearon ER, Cho KR, Nigro JM, Kern SE, Simons IW, Ruppert JM, Hamilton SR, Preisinger AC, Thomas G, Kinzler KW, Vogelstein B (1990) Identification of a chromosome 18q gene that is altered in colorectal cancers. Science 247:49–56PubMedGoogle Scholar
  13. Fishel R, Lescoe MK, Rao MRS, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R (1993) The human mutator gene homolog MSH2 and its association with hereditary non-polyposis colon cancer. Cell 75:1027–1038PubMedGoogle Scholar
  14. Francke U, Kung F (1976) Sporadic bilateral retinoblastoma and 13q-chromosomal deletion. Med Pediatr Oncol 2:379–385PubMedGoogle Scholar
  15. Francke U, Holmes LB, Atkins L, Riccardi VM (1979) Aniridia-Wilms' tumor association: evidence for specific deletion of 11p13. Cytogenet Cell Genet 24:185–192PubMedGoogle Scholar
  16. Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP (1986) A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323:643–646PubMedGoogle Scholar
  17. Fung Y-KT, Murphree AL, T'Ang A, Qian J, Hinrichs SH, Benedict WF (1987) Structural evidence for the authenticity of the human retinoblastoma gene. Science 236:1657–1661PubMedGoogle Scholar
  18. Futreal PA, Liu Q, Shattuck-Eidens D, Cochran C, Harshman K, Tavtigian S, Bennett LM, Haugen-Strano A, Swensen J, Miki Y, Eddington K, McClure M, Frye C, Weaver-Feldhaus J, Ding W, Gholami Z, Söderkvist P, Terry L, Jhanwar S, Berchuck A, Iglehart JD, Marks J, Ballinger DG, Barrett JC, Skolnick MH, Kamb A, Wiseman R (1994)BRCA1 mutations in primary breast and ovarian cancers. Science 266:120–122PubMedGoogle Scholar
  19. Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GAP (1990) Homozygous deletion in Wilms' tumours of a zinc-finger gene identified by chromosome jumping. Nature 343:774–778PubMedGoogle Scholar
  20. Godbout R, Dryja TP, Squire J, Gallie BL, Phillips RA (1983) Somatic inactivation of genes on chromosome 13 is a common event in retinoblastoma. Nature 304:451–453PubMedGoogle Scholar
  21. Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, Joslyn G, Stevens J, Spirio L, Robertson M, Sargeant L, Krapcho K, Wolff E, Burt R, Hughes JP, Warrington J, McPherson J, Wasmuth J, LePaslier D, Abderrahim H, Cohen D, Leppert M, White R (1991) Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66:589–600PubMedGoogle Scholar
  22. Harpaz N, Peck AL, Yin J, Fiel I, Hontanosas M, Tong TR, Laurin JN, Abraham JM, Greenwald BD, Meltzer SJ (1994) p53 protein expression in ulcertative colitis-associated colorectal dysplasia and carcinoma. Human Pathol 25:1069–1074Google Scholar
  23. Hashem N, Khalifa SH (1975) Retinoblastoma: a model of hereditary fragile chromosomal regions. Hum Hered 25:35–49PubMedGoogle Scholar
  24. Hethcote HW, Knudson AG (1978) Model for the incidence of embryonal cancers: application to retinoblastoma. Proc Natl Acad Sci USA 75:2453–2457PubMedGoogle Scholar
  25. Ichii S, Horii A, Nakatsuru S, Furuyama J, Utsunomiya J, Nakamura Y (1992) Inactivation of bothAPC alleles in an early stage of colon adenomas in a patient with familial adenomatous polyposis (FAP). Hum Mol Genet 1:387–390PubMedGoogle Scholar
  26. Kaneko Y, Egues MC, Rowley JD (1981) Interstitial deletion of short arm of chromosome 11 limited to Wilms' tumor cells in a patient without aniridia. Cancer Res 41:4577–4578PubMedGoogle Scholar
  27. Kastan MB, Zhan Q, El Deiry WS, Carrier F, Jacks T, Walsh WV, Plunkett BS, Vogelstein B, Fornace AJ (1992) A mammalian cell cycle checkpoint pathway utilizing p53 andGADD45 is defective in ataxia-telangiectasia. Cell 71:587–597PubMedGoogle Scholar
  28. Kikuchi-Yanoshita R, Konishi M, Ito S, Seki M, Tanaka K, Maeda Y, Iino H, Fukayama M, Koike M, Mori T, Sakuraba H, Fukunari H, Iwama T, Miyaki M (1992) Genetic changes of bothp53 alleles associated with the conversion from colorectal adenoma to early carcinoma in familial adenomatous polyposis. Cancer Res 52:3965–3971PubMedGoogle Scholar
  29. Klein G (1987) The approaching era of the tumor-suppressor genes. Science 238:1539–1545PubMedGoogle Scholar
  30. Knudson AG (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820–823PubMedGoogle Scholar
  31. Knudson AG (1973) Mutation and human cancer. Adv Cancer Res 17:317–352Google Scholar
  32. Knudson AG (1978) Retinoblastoma: a prototypic hereditary neoplasm. Semin Oncol 5:57–60PubMedGoogle Scholar
  33. Knudson AG (1985) Hereditary cancer, oncogenes, and antioncogenes. Cancer Res 45:1437–1443PubMedGoogle Scholar
  34. Knudson AG (1992) Stem cell regulation, tissue ontogeny, and oncogenic events. Sem. Cancer Biol 3:99–106Google Scholar
  35. Knudson AG (1993) Antioncogenes and human cancer. Proc Natl Acad Sci USA 90:10914–10921PubMedGoogle Scholar
  36. Knudson AG, Strong LC (1972a) Mutation and cancer: a model for Wilms' tumor of the kidney. J Natl Cancer Inst 48:313–324PubMedGoogle Scholar
  37. Knudson AG, Strong LC (1972b) Mutation and cancer: neuroblastoma and pheochromocytoma. Am J Hum Genet 24:514–532PubMedGoogle Scholar
  38. Knudson AG, Strong LC, Anderson DE (1973) Heredity and cancer in man. Prog Med Genet 9:113–158PubMedGoogle Scholar
  39. Knudson AG, Meadows AT, Nichols WW, Hill R (1976) Chromosomal deletion and retinoblastoma. N Engl J Med 295:1120–1123PubMedGoogle Scholar
  40. Koufos A, Hansen MF, Lampkin DB, Workman ML, Copeland NG, Jenkins NA, Cavenee WK (1984) Loss of alleles at loci on human chromosome 11 during genesis of Wilms' tumour. Nature 309:170–172PubMedGoogle Scholar
  41. Ladda R, Atkins L, Littlefield J, Neurath P, Marimuthu KM (1974) Computer-assisted analysis of chromosomal abnormalities: detection of a deletion in aniridia/Wilms' tumor syndrome. Science 185:784–787PubMedGoogle Scholar
  42. Lane DP, Crawford LW (1979) T antigen is bound to a host protein in SV40-transformed cells. Nature 278:261–263PubMedGoogle Scholar
  43. Leach FS, Nicolaides NC, Papadopoulos N, Liu B, Jen J, Parsons R, Peltomäki P, Sistonen P, Aaltonen LA, Nyström-Lahti M, Guan X-Y, Zhang J, Meltzer PS, Yu J-W, Kao F-T, Chen DJ, Cerosaletti KM, Fournier REK, Todd S, Lewis T, Leach RJ, Naylor SL, Weissenbach J, Mecklin J-P, Järvinen H, Petersen GM, Hamilton SR, Green J, Jass J, Watson P, Lynch HT, Trent JM, Chapelle A de la, Kinzler KW, Vogelstein B (1993) Mutations of a mutS homolog in hereditary non-polyposis colorectal cancer. Cell 75:1215–1225PubMedGoogle Scholar
  44. Lee W-H, Bookstein R, Hong F, Young L-J, Shew J-Y, Lee EY-HP (1987) Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science 235:1394–1399PubMedGoogle Scholar
  45. Li FP, Fraumeni JF (1975) Familial breast cancer, soft-tissue sarcomas, and other neoplasms. Ann Intern Med 83:833–834Google Scholar
  46. Linzer DIH, Levine AJ (1979) Characterization of a 54 K dalton cellular SV40 tumor antigen present in SV40 transformed cells and uninfected embryonal carcinoma cells. Cell 17:43–52PubMedGoogle Scholar
  47. Malkin D, Li FP, Strong LC, Fraumeni JF, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, Friend SH (1990) Germline p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:1233–1238PubMedGoogle Scholar
  48. Masuda HC, Miller C, Koeffler HP, Battifora H, Cline MJ (1987) Rearrangement of the p53 gene in human osteogenic sarcomas. Proc Natl Acad Sci USA 84:7716–7719PubMedGoogle Scholar
  49. Mulligan LM, Kwok JBJ, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, Ponder MA, Telenius H, Tunnacliffe A, Ponder BAJ (1993) Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363:458–460PubMedGoogle Scholar
  50. Naylor SL, Johnson BE, Minna JD, Sakaguchi AY (1987) Loss of heterozygosity of chromosome 3p markers in small-cell lung cancer. Nature 329:451–454PubMedGoogle Scholar
  51. Nishisho I, Nakamura Y, Miyoski Y, Miki Y, Ando H, Horii A, Koyama K, Utsunomiya J, Baba S, Hedge P, Markham A, Krush AJ, Petersen G, Hamilton SR, Nilbert MC, Levy DB, Bryan TM, Preisinger AC, Smith KJ, Su L-K, Kinzler KW, Vogelstein B (1991) Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253:665–669PubMedGoogle Scholar
  52. Orkin SH, Goldman DS, Sallan SE (1984) Development of homozygosity for chromosome 11p markers in Wilms' tumor. Nature 309:172–174PubMedGoogle Scholar
  53. Oshima M, Oshima H, Kitagawa K, Kobayashi M, Itakura C, Taketo M (1995) Loss ofApc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncatedApc gene. Proc Natl Acad Sci USA 92:4482–4486PubMedGoogle Scholar
  54. Papadopoulos N, Nicolaides NC, Wei YF, Ruben SM, Carter KC, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM, Adams MD, Venter JC, Hamilton SR, Petersen GM, Watson P, Lynch HT, Peltomäki P, Mecklin J-P, Chapelle A de la, Kinzler KW, Vogelstein B (1994) Mutation of a mutL homolog in hereditary colon cancer. Science 263:1625–1629PubMedGoogle Scholar
  55. Reeve AE, Housiaux PJ, Gardner RJM, Chewings WE, Grindley RM, Millow LJ (1984) Loss of Harveyras allele in sporadic Wilms' tumour. Nature 309:174–176PubMedGoogle Scholar
  56. Riccardi VM, Sujansky E, Smith AC, Francke U (1978) Chromosomal imbalance in the aniridia-Wilms' tumor association: 11p interstitial deletion. Pediatrics 61:604–610PubMedGoogle Scholar
  57. Smith KJ, Johnson KA, Bryan TM, Hill DE, Markowitz S, Willson JKV, Paraskeva C, Petersen GM, Hamilton SR, Vogelstein B, Kinzler KW (1993) TheAPC gene product in normal and tumor cells. Proc Natl Acad Sci USA 90:2846–2850PubMedGoogle Scholar
  58. Sparkes RS, Sparkes MC, Wilson MG, Towner JW, Benedict W, Murphree AL, Yunis JJ (1980) Regional assignment of genes for human esterase D and retinoblastoma to chromosome band 13q14. Science 208:1042–1044PubMedGoogle Scholar
  59. Sparkes RS, Murphree AL, Lingua RW, Sparkes MC, Field LL, Funderburk SJ, Benedict WF (1983) Gene for hereditary retinoblastoma assigned to human chromosome 13 by linkage to esterase D. Science 219:971–973PubMedGoogle Scholar
  60. Tarmin L, Yin J, Harpaz N, Kozam M, Noordzij J, Antonio L, Jiang H-Y, Chan O, Cymes K, Meltzer SJ (1995) Adenomatous polyposis coli gene mutations in ulcerative colitis-associated dysplasias and cancers versus sporadic colon neoplasms. Cancer Res 55:2035–2038PubMedGoogle Scholar
  61. Whang-Peng J, Kao-Shan CS, Lee EC (1982) Specific chromosome defect associated with human small-cell lung cancer: deletion 3p(14-23). Science 215:181–182PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • Alfred G. Knudson
    • 1
  1. 1.Institute for Cancer ResearchFox Chase Cancer CenterPhiladelphiaUSA

Personalised recommendations