The two-hit hypothesis, also known as the Knudson hypothesis, is the

hypothesis A hypothesis (: hypotheses) is a proposed explanation for a phenomenon. A scientific hypothesis must be based on observations and make a testable and reproducible prediction about reality, in a process beginning with an educated guess o ...

that most

tumor suppressor gene A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell (biology), cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results ...

s require both

allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...

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, ...

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 (physical form and structure), its developmental processes, its biochemical and physiological propert ...

change. It was first formulated by Alfred G. Knudson in 1971 and led indirectly to the identification of

s. Knudson won the 1998 Albert Lasker Clinical Medical Research Award for this work. Knudson performed a statistical analysis on cases of

retinoblastoma Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and 80% of retinoblastoma cas ...

, a

malignant tumor Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal ...

of the

retina The retina (; or retinas) is the innermost, photosensitivity, light-sensitive layer of tissue (biology), tissue of the eye of most vertebrates and some Mollusca, molluscs. The optics of the eye create a focus (optics), focused two-dimensional ...

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 RB1 may refer to: * Red Bull RB1, a Formula 1 car * Retinoblastoma protein Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common pr ...

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 Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cell (biology), cells are malignant transformation, transformed into cancer cells. The process is characterized by changes at the cellular, G ...

(the development of cancer) depended both on the mutation of

proto-oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

s (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 ...

) and on the inactivation of

s, 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 Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type ...

Related ideas

Field cancerization Field cancerization or field effect (also termed field change, field change cancerization, field carcinogenesis, cancer field effect or premalignant field defect) is a biological process in which large areas of cells at a tissue surface or withi ...

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 Chromothripsis is a mutational process by which up to thousands of clustered chromosomal rearrangements occur in a single event in localised and confined genomic regions in one or a few chromosomes, and is known to be involved in both cancer and c ...

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 A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most import ...

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 Menin is a protein that in humans is encoded by the ''MEN1'' gene. Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1 (MEN-1 syndrome) and has autosomal dominant inheritance. Variations in the MEN1 gene can ...

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

{{reflist Carcinogenesis