Knudson Hypothesis

The Knudson hypothesis (aka multiple-hit 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, and later formulated by Alfred G. Knudson in 1971. Knudson's work led indirectly to the identification of cancer-related genes. Knudson won the 1998 Albert Lasker Medical Research Award for this work.

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 tumor of the retina that 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 tumor 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 tumor could develop, explaining the age difference.

It was later found that carcinogenesis (the development of cancer) depended both on the activation of proto-oncogenes (genes that stimulate cell proliferation) and on the 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 keep the cancer in check; only damage to TSGs would lead to unchecked proliferation. On the converse, a damaged TSG (such as the Rb1 gene in retinoblastoma) would not lead to cancer unless there is uncontrolled growth from an activated oncogene.

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