A tumor suppressor gene, or antioncogene, is a gene that protects a cell from one step on the path to cancer. When this gene mutates to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes. The loss of these genes may be even more important than proto-oncogene/oncogene activation for the formation of many kinds of human cancer cells. Tumor suppressor genes can be grouped into categories including caretaker genes, gatekeeper genes, and landscaper genes; the classification schemes are evolving as medicine advances, learning from fields including molecular biology, genetics, and epigenetics.
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Two-hit hypothesis
Unlike oncogenes, tumor suppressor genes generally follow the "two-hit hypothesis," which implies that both alleles that code for a particular protein must be affected before an effect is manifested. This is because if only one allele for the gene is damaged, the second can still produce the correct protein. In other words, mutant tumor suppressors' alleles are usually recessive whereas mutant oncogene alleles are typically dominant.
The two-hit hypothesis was first proposed by A.G. Knudson for cases of retinoblastoma. 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 biallelic mutation. Oncogene mutations, in contrast, generally involve a single allele because they are gain-of-function mutations.
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 normal protein from the un-mutated allele.
Other tumor-suppressor genes that are exceptions to the "two-hit" rule are those that exhibit haploinsufficiency, including PTCH in medulloblastoma and NF1 in neurofibroma. An example of this is the p27Kip1 cell-cycle inhibitor, in which mutation of a single allele causes increased carcinogen susceptibility.
Functions
Tumor-suppressor genes, or more precisely, the proteins for which they code, either have a damping or repressive effect on the regulation of the cell cycle or promote apoptosis, and sometimes do both. The functions of tumor-suppressor proteins fall into several categories including the following:
- Repression of genes that are essential for the continuing of the cell cycle. If these genes are not expressed, the cell cycle does not continue, effectively inhibiting cell division.
- Coupling the cell cycle to DNA damage. As long as there is damaged DNA in the cell, it should not divide. If the damage can be repaired, the cell cycle can continue.
- If the damage cannot be repaired, the cell should initiate apoptosis (programmed cell death) to remove the threat it poses for the greater good of the organisms produced
- Some proteins involved in cell adhesion prevent tumor cells from dispersing, block loss of contact inhibition, and inhibit metastasis. These proteins are known as metastasis suppressors.
- DNA repair proteins are usually classified as tumor suppressors as well, as mutations in their genes increase the risk of cancer, for example mutations in HNPCC, MEN1 and BRCA. Furthermore, increased mutation rate from decreased DNA repair leads to increased inactivation of other tumor suppressors and activation of oncogenes.
Examples
The first tumor-suppressor protein discovered was the Retinoblastoma protein (pRb) in human retinoblastoma; however, recent evidence has also implicated pRb as a tumor-survival factor.
Another important tumor suppressor is the p53 tumor-suppressor protein encoded by the TP53 gene. Homozygous loss of p53 is found in 65% of colon cancers, 30–50% of breast cancers, and 50% of lung cancers. Mutated p53 is also involved in the pathophysiology of leukemias, lymphomas, sarcomas, and neurogenic tumors. Abnormalities of the p53 gene can be inherited in Li-Fraumeni syndrome (LFS), which increases the risk of developing various types of cancers.
PTEN acts by opposing the action of PI3K, which is essential for anti-apoptotic, pro-tumorogenic Akt activation.
As costs of DNA sequencing have diminished, many cancers have now been sequenced for the first time, revealing novel tumor suppressors. Among the most frequently mutated genes are components of the SWI/SNF chromatin remodeling complex, which are lost in about 20% of tumors.
Other examples of tumor suppressors include pVHL, APC, CD95, ST5, YPEL3, ST7, and ST14.