Knudson's hypothesis

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The Knudson hypothesis (two-hit hypothesis) is the assumption that cancer is the result of several consecutive mutations in the DNA of the affected cell. This assumption was first published by Carl O. Nordling in 1953 and later formulated by Alfred G. Knudson in 1971. Knudson's work indirectly led to the discovery of cancer genes . In 1998 he received the Albert Lasker Award for Clinical Medical Research .

Theodor Boveri postulated as early as 1914 that a combination of chromosomal defects leads to cancer development. He suspected that the loss (or defect) of two homologous parental chromosomes as a result of independent mutation events leads to the development of tumors. The so-called multi-mutation theory of cancer development was first published by Nordling in the British Journal of Cancer . Nordling noticed that in the industrialized nations the incidence of cancer increases with a power of 6 of the age of those affected. This relationship can be explained by the assumption that six consecutive mutations are necessary for a tumor to develop.

Knudson later undertook a statistical analysis of the number of cases of retinoblastoma , a tumor of the retina that occurs both as hereditary and as a sporadic form. He noted that the patients with the inherited form of the disease had a lower age at first and that these patients often developed a tumor in both eyes, suggesting a congenital predisposition . Knudson assumed that several mutation events were necessary to trigger the tumor. In children who show a hereditary form of retinoblastoma, the first mutation should be congenital and every subsequent event should greatly increase the risk of cancer development. In the sporadic form of the disease, two events should be necessary during the life of the patient, which would explain the later age of first disease.

It was later discovered that tumor development is associated with the activation of oncogenes and the deactivation of tumor suppressor genes . The first event with the activation of the oncogene will not necessarily lead to the development of a cancerous tumor as long as a tumor suppressor is active in the cell. Only damage to the tumor suppressor genes (in the case of retinoblastoma, inactivation of the RB1 gene) leads to the development of the disease.

literature

  • Knudson's two-hit hypothesis for tumorigenesis involving a tumor suppressor gene (TSG). In: Expert Reviews in Molecular Medicine. 2001 journals.cambridge.org (PDF).

Individual evidence

  1. ^ CO Nordling: A new theory on cancer-inducing mechanism . In: British Journal of Cancer . tape 7 , no. 1 , March 1953, p. 68-72 , PMID 13051507 , PMC 2007872 (free full text).
  2. ↑ B. Marte: Milestone 9: (1953) Two-hit hypothesis - It takes (at least) two to tango. In: Nature Milestones Cancer. April 1, 2006 ( nature.com ).
  3. ^ Alfred G. Knudson, Jr .: Mutation and cancer. Statistical study of retinoblastoma . In: Proceedings of the National Academy of Sciences . tape 68 , no. 4 , April 1971, p. 820-823 , PMID 5279523 , PMC 389051 (free full text).
  4. ↑ Theodor Boveri: On the question of the development of malignant tumors . In: Science . tape 40 , no. 1041 , December 11, 1914, p. 857–859 , doi : 10.1126 / science.40.1041.857 (Im Buch, Gustav Fischer, Jena 1914, pp. 29–32).