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Tumor Suppressor Genes are important genes that act within the genome to regulate several cellular functions. These genes can be broadly classified based on their role in cell growth/cell cycle progression, cell proliferation, DNA repair mechanisms, and other crucial cellular signaling functions such as the apoptosis induction. Without functional tumor suppressor genes, there is a high risk of dysregulated cell growth that is a well-known mechanism for the development of cancers. [rx] Loss of function mutations in tumor suppressor genes has been identified in many types of cancers, including ovarian, lung, colorectal, head and neck, pancreatic, uterine, breast, and bladder cancer.[rx][rx][rx][rx][rx] There are even familial cancer syndromes associated with the loss of function germline mutations of specific tumor suppressor genes like Li-Fraumeni syndrome with the loss of TP53.[rx] Extensive research is underway to understand these genes and their relationship to cancers to facilitate the development of novel targets for specific cancer types.
Most of our current knowledge of tumor suppressor genes originates from the initial studies of the retinoblastoma (RB) gene; this was the first tumor suppressor gene discovered, and mutations in RB cause childhood retinoblastoma. This disease is an inherited condition caused by an inactivating mutation in the RB1 gene that causes a 10,000-fold increased risk of developing retinoblastoma (often in both eyes) as compared to the general population. These patients are also at increased risk of developing osteosarcoma and other sarcomas. Interestingly, about 60% of retinoblastomas occur sporadically (almost always in one eye), and these patients are not at increased risk for other forms of cancer.[8] To explain this dichotomy, Knudson proposed a “two-hit” hypothesis:
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In the inherited form of retinoblastoma, children inherit one mutated RB allele (germ-line mutation), and the other copy is normal. Retinoblastoma develops when the normal retinoblastoma (RB) allele undergoes a spontaneous somatic mutation; this is the “second hit.”
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In sporadic cases of retinoblastoma, both normal RB alleles must undergo a somatic mutation in the same cell. The probability of this is low, which explains why retinoblastoma is uncommon in the general population. In both cases, the resulting two hits lead to the development of retinoblastoma.[9]
Based on these original observations, there are three important properties of classic tumor suppressor genes (TSGs):
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Classic tumor suppressor genes (TSGs) are recessive at the cellular level, with inactivation of both alleles typically found in tumors.
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Inheritance of a solitary mutant allele increases tumor susceptibility because only a single additional inactivating event is necessary for complete loss of gene function.
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The same gene is often inactivated in sporadic cancers.[rx]
Clinical Significance of Tumor Suppressor Genes
Mechanism
Tumor suppressor genes can be broadly divided into five types functionally [rx]:
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Genes that encode intracellular proteins that are crucial in controlling the progression of cell cycle stages – (e.g., pRB and p16)[rx]
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Genes that encode receptors or signal transducers which orchestrate signals that inhibit cell proliferation [e.g., adenomatous polyposis coli (APC) and transforming growth factor (TGF)-β][rx]
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Genes that encode the checkpoint-control proteins, which are useful in triggering cell cycle arrest in case of DNA damage or chromosomal defects [e.g., p16, p14, and breast cancer type 1 susceptibility protein (BRCA1)][rx]
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Genes that encode proteins useful for the induction of apoptosis (e.g., p53)[rx]
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Genes that encode proteins involved in the repair of DNA [e.g., DNA mismatch repair protein 2 (MSH2) and p53][rx]
Many tumor suppressor genes have been the object of studies, and there are likely many more that have yet to be discovered. The mechanisms of each tumor suppressor gene and its protein products are complex and interrelated to other cell signaling pathways, but some better-known mechanisms appear below.
Retinoblastoma (RB): RB gene, also called ‘Governor of the Cell Cycle,’ encodes the RB protein that, when hypophosphorylated, binds and inhibits E2F transcriptions factors.[rx] These transcription factors regulate genes that are essential for cells to pass from G1 to the S phase of the cell cycle. Typical growth factor signaling causes RB hyperphosphorylation and inactivation, thus causing cell cycle progression.[rx] A variety of mechanisms like loss-of-function mutations affecting RB, CDK4, and cyclin D gene amplification, cyclin-dependent kinase inhibitors loss (p16/INK4a), and inhibition of RB by the binding of viral oncoproteins (E7 protein of HPV) can revoke the antiproliferative effect of RB in cancers.[rx]
TP53 Tumor Suppressor Gene: The TP53 tumor suppressor gene is also known as the “guardian of the genome” as it serves to monitor for cellular stress like anoxia, identify DNA damage, or inappropriate signaling by mutated oncoproteins.[rx][rx] The TP53 gene encodes for the p53 protein, which controls the expression of proteins and their activity in cell cycle arrest, cellular senescence, DNA repair, and apoptosis. Loss of p53 can cause continued cell replication despite DNA damage and failure to activate programmed cell death.[rx] The DNA damage is perceived by complexes comprising kinases of the ATM/ATR family.[rx] These kinases phosphorylate p53, releasing it from inhibitors such as MDM2. The active p53 upregulated the expressions of important proteins like cyclin-dependent kinase inhibitor p21, which causes G1-S checkpoint arrest of the cell cycle. In instances where the DNA damage is not repairable, p53 induces events like activating the BAX gene, which encodes a pro-apoptotic protein that finally lead to cellular apoptosis or senescence. It also works to inhibit the BCL2 anti-apoptotic gene and stimulates the release of cytochrome c from the mitochondria. Cytochrome c activates caspases within the cell responsible for its eventual degradation. Similar to RB, p53 can be inactivated by viral oncoproteins like the E6 protein of HPV, thus revoking the antiproliferative and other important cellular effects. Most of the cancers demonstrate a biallelic loss-of-function mutation in TP53. Uncommon patients with Li-Fraumeni syndrome have a very high incidence of a wide variety of cancers like breast cancer, soft-tissue, and bone sarcomas, and brain tumors since they inherit one defective copy of TP53.[rx][rx][rx]
Phosphatase and Tensin Homolog (PTEN) Gene: PTEN gene encodes a lipid phosphatase that negatively regulates the phosphoinositide-3-kinase (PI3K)-AKT and the target of mTOR signaling pathways. These pathways are vital for cell proliferation, cell cycle progression, and apoptosis.[rx] The PTEN protein also functions to keep migration, adhesion, and angiogenesis in check. It also plays a role in the overall stabilization of the genome. A biallelic loss-of-function is common in diverse cancers. Cowden syndrome is an autosomal dominant disorder resulting from germline loss-of-function mutations of this gene and correlates with a higher risk of breast and endometrial cancer
CDH1 (E-cadherin): Normal cells stop proliferating once they come into contact with neighboring cells, which helps to maintain the structure and architecture of the tissue, referred to as contact inhibition. Mediation of cell-to-cell contact in many tissues is the function of a group of proteins called cadherins.[rx] E-cadherin (epithelial cadherin) regulates contact inhibition by binding to a key component of the WNT signaling pathway, ß-catenin. This binding prevents E-cadherin from translocating to the nucleus of the cell, stopping it from activating transcription of pro-growth target genes.[rx] Overall, this interaction regulates the morphology and organization of epithelial cell linings. Autosomal dominant familial gastric carcinoma is associated with a germline loss-of-function in this gene. [rx]
NF1 and NF2: NF1 gene encodes for neurofibromin 1, which is a GTPase that functions as a negative regulator of RAS. A germline loss of function mutation of this gene causes Neurofibromatosis type 1, an autosomal dominant disorder associated with the formation of neurofibromas, brain tumors like optic gliomas, and malignant nerve sheath tumors peripherally.[rx][rx] NF2 encodes neurofibromin 2 (also known as merlin), which is a cytoskeletal protein associated with contact inhibition. Loss of function mutations of this gene leads to neurofibromatosis type 2, which is also an autosomal dominant disorder associated with an increased risk of bilateral schwannomas among other tumors.[rx]
BRCA 1, BRCA 2, PARP-1: BRCA1 and BRCA2 are tumor suppressor genes that encode proteins involved in the repair of DNA double-strand breaks through the homologous recombination repair pathway.[rx] PARP-1 encodes a protein that assists with the repair of single-stranded breaks in the DNA. Without functional proteins that repair DNA, the cell cycle continues to pass along defective and mutated genetic material that leads to aberrant daughter cells.
APC: The APC gene encodes a tumor suppressor protein that negatively regulates the WNT signaling pathway. This regulation leads to enhancement of the formation of a complex that degrades β-catenin that is involved in the regulation and co-ordination of cell-cell adhesion and gene transcription.[rx][rx] The APC mutation is present in familial adenomatous polyposis, an autosomal dominant disorder where thousands of colonic polyps develop with early onset of colon carcinoma. The tumor development is associated with a loss of a single normal APC allele.
CDKN2A: This complex encodes two tumor suppressor proteins, p16/INK4a, and ARF, which augments RB function and stabilizes p53, respectively.[rx] Loss-of-function germline mutations in this gene occur in autosomal dominant familial melanoma. A biallelic loss-of-function presents in multiple cancers including melanomas, leukemias, and carcinomas.
WT1: WT1 gene encodes for transcription factors required for normal genitourinary tissue development. Wilms tumor, pediatric kidney cancer, is associated with a germline loss-of-function mutation in this gene. Sporadic Wilms tumor also correlates with similar WT1 mutations.[rx]
PTCH1: PTCH1 tumor suppressor gene encodes protein patched homolog 1 that negatively regulated the hedgehog signaling pathway.[rx][rx] Gorlin syndrome is an autosomal dominant disorder that correlates with a germline loss-of-function mutation in this gene and has a high risk of developing basal cell carcinoma and medulloblastoma. Sporadic cases of basal cell carcinoma and medulloblastomas are frequently associated with acquired biallelic loss-of-function PTCH1 mutations.[rx]
VHL: VHL gene encodes a component of a ubiquitin ligase, which is involved in the degradation of hypoxia-induced factors (HIFs). These are transcription factors that alter the expression of genes in response to hypoxia. Von Hippel-Lindau syndrome, an autosomal dominant disorder, is associated with loss-of-function germline mutations of this gene and poses a high risk of developing renal cell carcinoma and pheochromocytoma.[rx][rx]
Points to Remember
Tumor suppressor genes function to either repress or inhibit the cell cycle or promote apoptosis. The more specific functions of tumor suppressor proteins fall into several categories, including[rx[rx]:
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Inhibition of mitogenic signaling pathways
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Inhibition of cell cycle progression
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Inhibition of “pro-growth” programs of metabolism and angiogenesis
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Inhibition of invasion and metastasis
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Stabilization of the genome
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DNA repair factors
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Induction of apoptosis
