The Knudson hypothesis, also known as the two-hit hypothesis, is the
hypothesis
A hypothesis (plural hypotheses) is a proposed explanation for a phenomenon. For a hypothesis to be a scientific hypothesis, the scientific method requires that one can test it. Scientists generally base scientific hypotheses on previous obse ...
that most
tumor suppressor genes require both
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
s to be inactivated, either through
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s or through
epigenetic silencing, to cause a
phenotypic
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
change. It was first formulated by
Alfred G. Knudson
Alfred George Knudson, Jr. (August 9, 1922 – July 10, 2016) was an American physician and geneticist specializing in cancer genetics. Among his many contributions to the field was the formulation of the Knudson hypothesis in 1971, which exp ...
in 1971
and led indirectly to the identification of
tumor suppressor genes. Knudson won the 1998
Albert Lasker Clinical Medical Research Award
Lasker-DeBakey Clinical Medical Research Award is one of four annual awards presented by the Lasker Foundation. The Lasker-DeBakey award is given to honor outstanding work for the understanding, diagnosis, prevention, treatment, and cure of diseas ...
for this work.
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 two "hits" to DNA were necessary to cause the cancer. In the children with inherited retinoblastoma, the first mutation in what later came to be identified as the
RB1 gene, was inherited, the second one acquired. In non-inherited retinoblastoma, instead two mutations, or "hits", had to take place before a tumor could develop, explaining the later onset.
It was later found that
carcinogenesis (the development of cancer) depended both on the mutation of
proto-oncogenes (genes that stimulate
cell proliferation
Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...
) and on the inactivation of
tumor suppressor genes, which are genes that keep proliferation in check. Knudson's hypothesis refers specifically, however, to the heterozygosity of tumor suppressor genes. An inactivation of both alleles is required, as a single functional tumor suppressor gene 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, which is termed
haploinsufficiency.
Related ideas
Field cancerization may be an extended form of the Knudson hypothesis. This is the phenomenon of various primary tumors 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
Wilms tumor protein (WT33) is a protein that in humans is encoded by the ''WT1'' gene on chromosome 11p.
Function
This gene encodes a transcription factor that contains four zinc finger motifs at the C-terminus and a proline / glutamine-rich ...
),
but based on these genes following the Knudson "two-hit" hypothesis, they are strongly presumed to be suppressor genes.
References
{{Use dmy dates, date=May 2011
Carcinogenesis