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CDKN2A
cyclin dependent kinase inhibitor 2A
The CDKN2A gene provides instructions for producing proteins that act as tumour suppressors, playing a crucial role in preventing uncontrolled cell growth. CDKN2A is fundamental for regulating the cell cycle and safeguarding against tumour development.
CDKN2A is located on the short (p) arm of chromosome 9, at band 9p21.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The CDKN2A gene, also known as cyclin dependent kinase inhibitor 2A, is a significant gene in human genetics due to its role as a tumour suppressor. It encodes for multiple protein products, notably p16(INK4a) and p14(ARF), which are involved in controlling cell division and preventing the formation of tumours. These proteins act as critical checkpoints, ensuring cells divide in a regulated manner and stopping the proliferation of damaged or overly dividing cells.
Disruptions to CDKN2A's function, often through genetic mutations, can compromise these protective mechanisms. Such changes are implicated in various human cancers, making CDKN2A a key focus in cancer genetics research and clinical screening. Understanding its function helps clarify the genetic basis of several inherited cancer predispositions.
What the gene does
The CDKN2A gene produces two primary tumour suppressor proteins: p16(INK4a) and p14(ARF), both essential for regulating cell proliferation and preventing tumour development. The p16(INK4a) protein functions by binding to cyclin-dependent kinases such as CDK4 and CDK6. These kinases normally promote cell cycle progression towards division. By inhibiting CDK4 and CDK6, p16(INK4a) prevents cells from dividing too rapidly or uncontrollably, effectively halting the cell cycle when necessary. This inhibitory action is crucial for maintaining cellular homeostasis and preventing genomic instability [PMID:17962459].
The p14(ARF) protein operates through a different mechanism, primarily by stabilising another crucial tumour suppressor protein, p53. The p53 protein is vital for coordinating cell division, triggering cellular senescence (a state of permanent growth arrest), and initiating apoptosis (programmed cell death) in compromised cells. By protecting p53 from degradation, p14(ARF) enhances the tumour-suppressing capabilities of p53, thereby contributing to the prevention of abnormal cell growth and tumour formation [PMID:10207062]. Both p16(INK4a) and p14(ARF) are often upregulated in cells that are no longer capable of division, serving as an important checkpoint against uncontrolled cellular expansion [PMID:10207062].
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Chromosome location
The CDKN2A gene is situated on chromosome 9 at position 9p21.3. This specific location refers to the p arm of chromosome 9, bands 21.3. The gene's placement on the chromosome is significant, as this region is frequently observed to have deletions or alterations in various human cancers. The CDKN2A gene consists of multiple exons, which are segments of DNA that contain instructions for protein synthesis.
Protein structure
The CDKN2A gene encodes for a protein product with a length of 156 amino acids. This protein contains several key structural motifs known as ankyrin repeats, which are common protein-protein interaction modules. Specifically, the CDKN2A protein features four ankyrin repeat domains. These include ANK 1 (Repeat), spanning amino acids 11-40; ANK 2 (Repeat), located from amino acids 44-72; ANK 3 (Repeat), found at amino acids 77-106; and ANK 4 (Repeat), extending from amino acids 110-139. These ankyrin repeats are critical for the protein's ability to interact with other molecules in the cell, facilitating its role in cell cycle regulation and tumour suppression.
Key variants
Genetic variations within the CDKN2A gene can range from single nucleotide changes to larger deletions or duplications. Pathogenic variants, which impair gene function, are often associated with an elevated risk for specific cancers. These variations can affect the production of the p16(INK4a) or p14(ARF) proteins, or alter their function, subsequently disrupting crucial cell cycle control mechanisms. Familial melanoma, linked to CDKN2A, typically follows an autosomal dominant inheritance pattern, meaning inheriting one altered copy of the gene is sufficient to increase a person's disease risk.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.106del | p.Ala36fs | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.106dup | p.Ala36fs | Pathogenic | ★★☆☆ | not provided |
c.122_123delinsT | p.Pro41fs | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.126dup | p.Ser43Ter | Pathogenic | ★★☆☆ | Familial melanoma |
c.131_132insAA | p.Tyr44Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.131dup | p.Tyr44Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.132C>A | p.Tyr44Ter | Pathogenic | ★★☆☆ | Familial melanoma |
c.132C>G | p.Tyr44Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.132del | p.Ser43_Tyr44insTer | Pathogenic | ★★☆☆ | Familial melanoma |
c.135dup | p.Arg46fs | Pathogenic | ★★☆☆ | Familial melanoma |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variations in the CDKN2A gene are primarily associated with an increased predisposition to various cancers. Germline mutations in CDKN2A are a significant genetic factor for Familial melanoma, an inherited form of skin cancer where multiple family members develop melanoma. These mutations are found in up to 40 percent of familial melanoma cases. The CDKN2A gene is also associated with Melanoma (polygenic risk), a complex genetic condition. Some research also suggests an association with hereditary pancreatic cancer.
Inheritance pattern
Conditions caused by pathogenic CDKN2A variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
CDKN2A is well-recognised within the UK's National Health Service (NHS) Genomic Medicine Service. The gene is included in several NHS England National Genomic Test Directory panels, indicating its clinical importance for diagnosing and managing inherited conditions. It is listed as 'green' in Adult solid tumours cancer susceptibility, Adult solid tumours for rare disease, Childhood solid tumours, Familial melanoma (R254), Familial tumours of the nervous system (R221), Inherited pancreatic cancer (R367), Melanoma pertinent cancer susceptibility, and Pigmentary skin disorders (R236).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Research suggests that certain lifestyle factors might interact with genetic predispositions, including those involving the CDKN2A gene. For individuals with an increased genetic risk for melanoma due to CDKN2A variants, practices such as rigorous sun protection, avoiding excessive UV exposure, and regular skin checks are generally recommended. For pancreatic cancer risk, maintaining a healthy weight, avoiding smoking, and limiting alcohol intake are lifestyle choices that may contribute to overall health. These general population health recommendations should not be seen as a substitute for professional medical advice or specific clinical management plans.
Supplement considerations
Currently, there is no conclusive scientific evidence to suggest that specific dietary supplements can prevent or treat conditions associated with CDKN2A gene variants. Scientific studies have not established a direct link where supplementation can negate the genetic predisposition or alter the course of associated cancers. Individuals concerned about their health or genetic risks should always consult with a healthcare professional before deciding to take any supplements, as some may interact with medications or have unintended effects.
Frequently asked questions
What is the primary function of the CDKN2A gene?
The CDKN2A gene produces tumour suppressor proteins, principally p16(INK4a) and p14(ARF), which regulate the cell cycle and prevent cells from growing and dividing too rapidly or uncontrollably, thereby helping to stop tumour formation.
Which medical conditions are primarily associated with CDKN2A variants?
CDKN2A gene variants are primarily associated with an increased risk for Familial melanoma and Melanoma (polygenic risk). There is also research suggesting potential involvement in hereditary pancreatic cancer.
How does the p16(INK4a) protein work?
The p16(INK4a) protein functions by binding to and inhibiting specific cyclin-dependent kinases (CDK4 and CDK6). This action blocks their ability to stimulate cell cycle progression, thereby controlling cell division and preventing uncontrolled cell growth.
What is the role of the p14(ARF) protein?
The p14(ARF) protein protects the important tumour suppressor protein p53 from being broken down. By stabilising p53, p14(ARF) helps in regulating cell division, senescence, and apoptosis, which are crucial for preventing tumour formation.
Is the CDKN2A gene recognised clinically in the UK?
Yes, the CDKN2A gene is recognised within the NHS Genomic Medicine Service and is included in several National Genomic Test Directory panels, indicating its clinical relevance for various cancer predispositions.
References
- He S, Sharpless NE. Senescence in Health and Disease. Cell. 2017. PMID: 28575665
- Taylor NJ, Mitra N, Goldstein AM. Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families. The Journal of investigative dermatology. 2017. PMID: 28830827
- Baker DJ, Childs BG, Durik M. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016. PMID: 26840489
- Lim AM, Do H, Young RJ. Differential mechanisms of CDKN2A (p16) alteration in oral tongue squamous cell carcinomas and correlation with patient outcome. International journal of cancer. 2014. PMID: 24436120
- Mountzios G, Rampias T, Psyrri A. The mutational spectrum of squamous-cell carcinoma of the head and neck: targetable genetic events and clinical impact. Annals of oncology : official journal of the European Society for Medical Oncology. 2014. PMID: 24718888
- Potrony M, Puig-Butillé JA, Aguilera P. Increased prevalence of lung, breast, and pancreatic cancers in addition to melanoma risk in families bearing the cyclin-dependent kinase inhibitor 2A mutation: implications for genetic counseling. Journal of the American Academy of Dermatology. 2014. PMID: 25064638
- Loyo M, Li RJ, Bettegowda C. Lessons learned from next-generation sequencing in head and neck cancer. Head & neck. 2013. PMID: 22907887
- Jeck WR, Siebold AP, Sharpless NE. Review: a meta-analysis of GWAS and age-associated diseases. Aging cell. 2012. PMID: 22888763
- Stransky N, Egloff AM, Tward AD. The mutational landscape of head and neck squamous cell carcinoma. Science (New York, N.Y.). 2011. PMID: 21798893
- Cánepa ET, Scassa ME, Ceruti JM. INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions. IUBMB life. 2007. PMID: 17654117
- Goldstein AM, Chan M, Harland M. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer research. 2006. PMID: 17047042