Cyclin-dependent kinase inhibitor-2A (CDKN2A)
Cyclin-dependent kinase inhibitor-2A (CDKN2A) is a critical tumor-suppressor gene located on chromosome 9p21.3, known for its role in regulating the cell cycle and preventing uncontrolled cell division. The gene produces proteins p16INK4a and p14ARF, which inhibit cyclin-dependent kinases (CDKs), essential for cell cycle progression. Disruption of CDKN2A function can lead to various cancers, as its inactivation is often associated with homozygous deletions, mutations, or methylation of the promoter.
Significantly, mutations in the CDKN2A gene have been linked to an increased risk of several types of cancer, including melanoma and pancreatic cancer. Individuals with CDKN2A mutations are at a heightened risk for developing melanoma, with estimates indicating a 28% to 67% increased likelihood. This association has led to the identification of Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome, highlighting the hereditary nature of these mutations.
Families with a history of both pancreatic cancer and melanoma are encouraged to participate in clinical screening for CDKN2A mutations, which can aid in assessing risk and improving outcomes for affected individuals. Importantly, there is a 50% chance that children of individuals with CDKN2A mutations will inherit the same mutation, emphasizing the need for awareness and genetic counseling.
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Cyclin-dependent kinase inhibitor-2A (CDKN2A)
ALSO KNOWN AS: CDKN2, multiple tumor suppressor 1 (MTS1), TP16, MLM, p16INK4a, p14ARF, cyclin-dependent kinase inhibitor 2A
DEFINITION: Cyclin-dependent kinase inhibitor-2A (CDKN2A) is a tumor-suppressor gene located on chromosome 9p21.3.
The gene’s role: As a tumor-suppressor gene, CDKN2A plays a major role in regulating cell division. The loss of function of a tumor-suppressor gene is a key event in the multistep process that transforms a normal cell into a cancer cell. In normal cells, the proteins that arise from these genes play a role in regulating cell growth and proliferation. A loss of function of these genes by mutation results in uncontrolled cell growth that leads to cancer. The chromosomal region where CDKN2A is located is often mutated in cancer cells.
The CDKN2A gene locus on chromosome 9p21 codes for the proteins p16INK4a and p14ARF, both of which inhibit the cell cycle. Cyclin-dependent kinases (CDKs) have two subunitsa kinase subunit (CDK) and a cyclin that activates the kinase. Regulating the function of CDKs is another group of proteins known as cyclin kinase inhibitors. The protein coded for by CDKN2A belongs to the cyclin-dependent kinase inhibitor family of proteins. It binds to CDKs and acts as an inhibitor of cell division. Disruption of the function of the CDKN2A gene, therefore, has major consequences on the normal functioning of a cell.
Cancer and the gene: Unlike other tumor-suppressor genes that are inactivated by point mutations, inactivation of CDKN2A occurs through homozygous deletions, mutations, or promoter methylation. Mutations in the CDKN2A gene are known to occur in patients with multiple primary myelomas. Inactivation of CDKN2A has also been reported in numerous primary tumors, including bladder carcinoma, glioma, mesothelioma, gastric lymphoma, Burkitt's lymphoma, T-cell acute lymphoblastic leukemia, melanoma, colorectal cancer, prostate adenocarcinoma, oral cancers, non-small cell lung carcinoma, and renal cell carcinoma. Some gene alterations that have been observed in different cancers related to alteration in the structure or function of CDKN2A include hypermethylation of CDKN2A in gastrinomas, germ-line mutation in CDKN2A in pancreatic cancer and melanoma, and inactivation of CDKN2A in sporadic pancreatic cancers.
An increased risk of and pancreatic cancer exists in individuals with CDKN2A mutations. The presence of this gene mutation is called Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome. CDKN2A mutations increase an individual's risk of melanoma by 28 to 67 percent. Clinical observations such as the detection of germ-line mutations in CDKN2A in melanoma-prone families, increased risk of pancreatic cancer among melanoma-prone families with CDKN2A mutations, and zero occurrence of pancreatic cancer in melanoma-prone families without the CDKN2A germ-line mutation suggest a link between CDKN2A mutations and occurrence of melanoma and pancreatic cancer. Families with co-occurrence of pancreatic cancer and melanoma should participate in clinical screening programs for CDKN2A mutations. This would enable the identification of high-risk family members and a more improved individual risk assessment for better outcomes for CDKN2A mutation carriers. It is understood that children of individuals with this gene mutation have a 50 percent chance of having the same gene mutation.
Bibliography
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