Tumor suppressor gene

A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a 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 in a loss or reduction in its function. In combination with other genetic mutations, this could allow the cell to grow abnormally. The loss of function for these genes may be even more significant in the development of human cancers, compared to the activation of oncogenes.

TSGs can be grouped into the following categories: caretaker genes, gatekeeper genes, and more recently landscaper genes. Caretaker genes ensure stability of the genome via DNA repair and subsequently when mutated allow mutations to accumulate. Meanwhile, gatekeeper genes directly regulate cell growth by either inhibiting cell cycle progression or inducing apoptosis. Lastly, landscaper genes regulate growth by contributing to the surrounding environment, and when mutated, can cause an environment that promotes unregulated proliferation. The classification schemes are evolving as medical advances are being made from fields including molecular biology, genetics, and epigenetics.

The discovery of oncogenes and their ability to deregulate cellular processes related to cell proliferation and development appeared first in the literature as opposed to the idea of tumor suppressor genes. However, the idea of genetic mutation leading to increased tumor growth gave way to another possible genetic idea of genes playing a role in decreasing cellular growth and development of cells. This idea was not solidified until experiments by Henry Harris were conducted with somatic cell hybridization in 1969.

Within Harris's experiments, tumor cells were fused with normal somatic cells to make hybrid cells. Each cell had chromosomes from both parents and upon growth, a majority of these hybrid cells did not have the capability of developing tumors within animals. The suppression of tumorigenicity in these hybrid cells prompted researchers to hypothesize that genes within the normal somatic cell had inhibitory actions to stop tumor growth. This initial hypothesis eventually lead to the discovery of the first classic tumor suppressor gene by Alfred Knudson, known as the Rb gene, which codes for the retinoblastoma tumor suppressor protein.

Alfred Knudson, a pediatrician and cancer geneticist, proposed that in order to develop retinoblastoma, two allelic mutations are required to lose functional copies of both the Rb genes to lead to tumorigenicity. Knudson observed that retinoblastoma often developed early in life for younger patients in both eyes, while in some rarer cases retinoblastoma would develop later in life and only be unilateral. This unique development pattern allowed Knudson and several other scientific groups in 1971 to correctly hypothesize that the early development of retinoblastoma was caused by inheritance of one loss of function mutation to an RB germ-line gene followed by a later de novo mutation on its functional Rb gene allele. The more sporadic occurrence of unilateral development of retinoblastoma was hypothesized to develop much later in life due to two de novo mutations that were needed to fully lose tumor suppressor properties. This finding formed the basis of the two-hit hypothesis. In order to verify that the loss of function of tumor suppressor genes causes increased tumorigenicity, interstitial deletion experiments on chromosome 13q14 were conducted to observe the effect of deleting the loci for the Rb gene. This deletion caused increased tumor growth in retinoblastoma, suggesting that loss or inactivation of a tumor suppressor gene can increase tumorigenicity.

Unlike oncogenes, tumor suppressor genes generally follow the two-hit hypothesis, which states both alleles that code for a particular protein must be affected before an effect is manifested. If only one allele for the gene is damaged, the other can still produce enough of the correct protein to retain the appropriate function. In other words, mutant tumor suppressor alleles are usually recessive, whereas mutant oncogene alleles are typically dominant^{[citation needed]}.

Proposed by A.G. Knudson for cases of retinoblastoma. He observed that 40% of U.S cases were caused by a mutation in the germ-line. However, affected parents could have children without the disease, but the unaffected children became parents of children with retinoblastoma. This indicates that one could inherit a mutated germ-line but not display the disease. Knudson observed that the age of onset of retinoblastoma followed 2nd order kinetics, implying that two independent genetic events were necessary. He recognized that this was consistent with a recessive mutation involving a single gene, but requiring bi-allelic mutation. Hereditary cases involve an inherited mutation and a single mutation in the normal allele. Non-hereditary retinoblastoma involves two mutations, one on each allele. Knudson also noted that hereditary cases often developed bilateral tumors and would develop them earlier in life, compared to non-hereditary cases where individuals were only affected by a single tumor.

There are exceptions to the two-hit rule for tumor suppressors, such as certain mutations in the p53 gene product. p53 mutations can function as a dominant negative, meaning that a mutated p53 protein can prevent the function of the natural protein produced from the non-mutated allele. Other tumor-suppressor genes that do not follow the two-hit rule are those that exhibit haploinsufficiency, including PTCH in medulloblastoma and NF1 in neurofibroma. Another example is p27, a cell-cycle inhibitor, that when one allele is mutated causes increased carcinogen susceptibility.