Knudson hypothesis

The Knudson hypothesis is the hypothesis that cancer is the result of accumulated mutations to a cell's DNA. It was first proposed by Carl O. Nordling in 1953,^[1][2] and later formulated by Alfred G. Knudson in 1971.^[3] Knudson's work led indirectly to the identification of cancer-related genes. Knudson won the 1998 Albert Lasker Medical Research Award for this work.

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The multi-mutation theory on cancer was proposed by Nordling in the British Journal of Cancer in 1953. He noted that in industrialized nations the frequency of cancer seems to increase according to the sixth power of age. This correlation could be explained by assuming that the outbreak of cancer requires the accumulations of six consecutive mutations.

Later, Knudson performed a statistical analysis on cases of retinoblastoma, a tumour of the retina which occurs both as an inherited disease and sporadically. He noted that inherited retinoblastoma occurs at a younger age than the sporadic disease. In addition, the children with inherited retinoblastoma often developed the tumour in both eyes, suggesting an underlying predisposition.

Knudson suggested that multiple "hits" to DNA were necessary to cause cancer. In the children with inherited retinoblastoma, the first insult was inherited in the DNA, and any second insult would rapidly lead to cancer. In non-inherited retinoblastoma, two "hits" had to take place before a tumour could develop, explaining the age difference.

It was later found that carcinogenesis (the development of malignancy) depended both on the activation of oncogenes (genes that stimulate cell proliferation) and deactivation of tumor suppressor genes (genes that keep proliferation in check). A first "hit" in an oncogene would not necessarily lead to cancer, as normally functioning tumor suppressor genes (TSGs) would still counterbalance this impetus; only damage to TSGs would lead to unchecked proliferation. Conversely, a damaged TSG (such as the Rb1 gene in retinoblastoma) would not lead to cancer unless there is a growth impetus from an activated oncogene.

Field cancerisation may be an extended form of the Knudson hypothesis. This is the phenomenon of various primary tumours developing in one particular area of the body, suggesting that an earlier "hit" predisposed the whole area for malignancy.

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