Alfred Knudson: Two Hits Times 25 Years | JNCI: Journal …

Alfred Knudson: Two Hits Times 25 Years ..

proposed his famous “two-hit” hypothesis of tumor suppression

The Knudson two-hit model explains the tremendously high prevalence ofcertain tumors in peopleunfortunate enough to have inherited one defective copy of atumor suppressor gene.

Genetic analysis of tumor samples has also complemented the statistical analysis to reaffirm the two hits in tumor development.

Posts about two hit hypothesis written ..

Dr. Knudson soon advanced this hypothesis and proposed that the two mutational hits take place in the two alleles of the same recessive gene (1973) that he termed “anti-oncogene” (1982). He also predicted that the second event could be caused by mutation, deletion, chromosomal loss, recombination etc. This was proven by the other researchers in 1983, which led to the identification of RB1 as a tumor suppressor and its cloning in 1986.

Retinoblastoma results when a mutation damages BOTH COPIES the healthy tumor-suppressor genein a single cell (the Knudson

It is difficult to identify substances potentially toxic to these systems for three interrelated reasons: first, these are among the most complex biological systems in humans, and animal models of reproductive and neurological function are generally acknowledged to be inadequate for representing such critical events as cognition or early embryofoetal development; second, there are no simple tests for identifying potential reproductive or neurological toxicants; and third, these systems contain multiple cell types and organs, such that no single set of mechanisms of toxicity can be used to infer dose-response relationships or predict structure-activity relationships (SAR). Moreover, it is known that the sensitivity of both the nervous and reproductive systems varies with age, and that exposures at critical periods may have much more severe effects than at other times.

'Loss of Heterozygosity' and 'Two Hit Hypothesis'


two-hit hypothesis; multiple-hit hypothesis; edit

Is a rare, but well known disease. It is a typical example of hereditary disposition of tumors. Knudson's two-hit hypothesis theory was proposed based on the epidemiologic studies of retinoblastoma. It is associated with mutations in the Rb protein. Rb mutations are recessive on the cellular level, but dominant on the level of the whole organism. A hereditary mutation in Rb (13q14) predisposes the individual towards generation of retinoblastoma (a malignant tumor of retina) in a low age. In addition to this, barers of the RB mutation are also predisposed towards osteosarcomas.

Dr. Knudson and the Two-Hit Theory | Fox Chase …

The cancer preventing effects of tumour suppressors usually require the presence of at least one functional gene. Therefore both copies of a tumour suppressor gene have to be inactivated. Prototypic tumor suppressor genes are therefore recessive and reguire "two-hit" inactivation of both alleles. Alfred Knudson (1971) proposed this two-hit model of tumor suppressor inactivation. Knudson deduced that in case gene inactivation is a random process, people who inherit an inactivated copy of a tumor suppressor gene have a higher risk of developing associated forms of cancer than people born with two normal copies. It was shown that in tumors in these predisposed patients, the remaining wild-type copy of the tour suppressr gene was lost. The process of losing the last functional allele is referred to as loss heterozygosity (LOH).

Knudson two-hit hypothesis of tumorigenesis.

Dr. Knudson who was trained as a physician and geneticist, focused on retinoblastoma patients who develop the tumor of the retina mostly in infancy, and often bilaterally. Using a statistical method, he found that bilateral hereditary cases fit for a one-hit phenomenon. The unilateral cases with no family history showed a distribution of two mutations. Because the hereditary form already harbored a germline mutation, both hereditary and nonhereditary forms of the tumor entailed the same number of events; hence “two-hit” hypothesis (1971).

proposed this two-hit model of tumor suppressor ..

Our lab subsequently used the Knudson two-hit hypothesis of tumorigenesis to provide the first evidence that the also functions as a tumor suppressor (). Since IGF2R is imprinted (i.e. one copy of the gene silenced by DNA methylation), this finding thrusted me into the rapidly growing research field of . Interestingly, I had the honor of finally meeting Dr. Knudson almost a decade later in Stockholm, Sweden at the 2004 Nobel Symposium on epigenetics entitled, . I will greatly miss these pioneering scientists upon whose shoulders I stood.