Knudson hypothesis

The Knudsonhypothese the assumption that cancer is the result of several successive mutations in the DNA of the affected cell. This assumption was first published by Carl O. Nordling 1953. and later formulated by Alfred G. Knudson in 1971. Knudson 's work led indirectly to the discovery of cancer genes. He was awarded the 1998 Albert Lasker Award for Clinical Medical Research.

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

Later, Knudson undertook a statistical analysis of the number of cases of retinoblastoma, a tumor of the retina that occurs as hereditary and sporadic than form. He noted that the age of onset of patients in the case of the hereditary form of the disease was lower and that these patients often developed a tumor in both eyes, which suggests an innate predisposition. Knudson assumed that multiple mutational events are necessary to induce the tumor. For the children who show an inherited form of retinoblastoma, the first mutation should therefore be innate and each additional event greatly increase the risk of cancer development. In the sporadic form of the disease should be necessary during the life of the patients two events, which would explain the later age of onset.

Later it was discovered that the tumor formation is accompanied by the activation of oncogenes and deactivation of tumor suppressor genes. The first event with the activation of the oncogene will not necessarily lead to the development of a cancer Geschwulstes as long as a tumor suppressor in the cell is active. Only a damage of the tumor suppressor genes ( in the case of inactivation of the retinoblastoma gene, RB1 ) leads to the formation of the disease.