The Knudson hypothesis, also known as the two-hit hypothesis or 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 Clinical 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 (TSG), which are genes that keep proliferation in check. Knudson's hypothesis refers specifically, however, to the heterozygosity of tumor suppressor genes. A mutation in both alleles is required, as a single functional TSG is usually sufficient. Some tumor suppressor genes have been found to be "dose-dependent" so that inhibition of one copy of the gene (either via genetic or epigenetic modification) may encourage a malignant phenotype.
Related ideas
Field cancerization 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 cancer.
Announced in 2011, chromothripsis similarly involves multiple mutations, but asserts that they may all appear at once. This idea, affecting only 2–3% of cases of cancer, although up to 25% of bone cancers, involves the catastrophic shattering of a chromosome into tens or hundreds of pieces and then being patched back together incorrectly. This shattering, it is presumed, takes place when the chromosomes are compacted during normal cell division, but the trigger for the shattering is unknown. Under this model, cancer arises as the result of a single, isolated event, rather than the slow accumulation of multiple mutations.
The exact function of some tumor suppressor genes is not currently known (e.g. MEN1, WT1), but based on these genes following the Knudson "two-hit" hypothesis, they are strongly presumed to be suppressor genes.