Knudson hypothesis
Encyclopedia
The Knudson hypothesis is the hypothesis
that cancer
is the result of accumulated mutation
s 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 gene
s. 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 gene
s (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.
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.
Hypothesis
A hypothesis is a proposed explanation for a phenomenon. The term derives from the Greek, ὑποτιθέναι – hypotithenai meaning "to put under" or "to suppose". For a hypothesis to be put forward as a scientific hypothesis, the scientific method requires that one can test it...
that cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
is the result of accumulated mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s to a cell's DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
. It was first proposed by Carl O. Nordling
Carl O. Nordling
Carl O. Nordling was a Finnish born architect, urban planner and amateur historian. He graduated as an architect from the Helsinki University of Technology in 1939 and immigrated to Sweden after the end of the Continuation War in 1944.As a statistician, he applied statistical methods to a number...
in 1953, and later formulated by Alfred G. Knudson
Alfred G. Knudson
Alfred George Knudson, Jr. M.D., Ph.D. is a geneticist specializing in cancer genetics. Among his many contributions to the field was the formulation of the Knudson hypothesis in 1971, which explains the effects of mutation on carcinogenesis .Born in Los Angeles in 1922, Knudson received his B.S...
in 1971. Knudson's work led indirectly to the identification of cancer-related gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s. 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
British Journal of Cancer
The British Journal of Cancer a twice-monthly professional medical journal of Cancer Research UK , published on their behalf by the Nature Publishing Group ....
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
Retinoblastoma
Retinoblastoma is a rapidly developing cancer that develops in the cells of retina, the light-detecting tissue of the eye. In the developed world, Rb has one of the best cure rates of all childhood cancers , with more than nine out of every ten sufferers surviving into...
, a tumor of the retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
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
Carcinogenesis
Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...
(the development of cancer) depended both on the activation of proto-oncogenes (genes that stimulate cell proliferation) and on the deactivation of tumor suppressor gene
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
s (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.
Related ideas
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 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
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
, 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.