The CDKN2A gene provides instructions for making several proteins. The most well-studied are the p16(INK4A) and the p14(ARF) proteins. Both function as tumor suppressors, which means they keep cells from growing and dividing too rapidly or in an uncontrolled way. Both proteins are also involved in stopping cell division in older cells (senescence).
The p16(INK4A) protein attaches (binds) to two other proteins called CDK4 and CDK6. These proteins help regulate the cell cycle, which is the cell's way of replicating itself in an organized, step-by-step fashion. CDK4 and CDK6 normally stimulate the cell to continue through the cycle and divide. However, binding of p16(INK4A) blocks CDK4's or CDK6's ability to stimulate cell cycle progression. In this way, p16(INK4A) controls cell division. Cells begin to produce p16(INK4A) when they are no longer able to undergo cell division.
The p14(ARF) protein protects a different protein called p53 from being broken down. The p53 protein is an important tumor suppressor that is essential for regulating cell division, senescence, and self-destruction (apoptosis). By protecting p53, p14(ARF) also helps prevent tumor formation. The p14(ARF) and p53 proteins are often made in cells that are unable to undergo cell division.
Health Conditions Related to Genetic Changes
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Head and neck squamous cell carcinoma
Mutations in the CDKN2A gene are found in up to one-quarter of head and neck squamous cell carcinomas (HNSCC). This type of cancerous tumor occurs in the moist lining of the mouth, nose, and throat. CDKN2A gene mutations associated with this condition are acquired during a person's lifetime and are found only in tumor cells; these changes are known as somatic mutations. Most of these mutations lead to production of little or no functional p16(INK4A) protein. Without p16(INK4A) to regulate cell growth and division (proliferation), cells can continue to grow and divide without control, which can lead to tumor formation.
A different type of alteration involving the CDKN2A gene can result in reduced amounts or an absence of the p16(INK4A) or p14(ARF) protein. This alteration, known as promoter hypermethylation, turns off the production of p16(INK4A) or p14(ARF). Without one of these tumor suppressors, cells can grow and divide unchecked, leading to the development of cancer.More About This Health Condition
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Mutations in the CDKN2A gene are also associated with melanoma, a type of skin cancer that begins in pigment-producing cells called melanocytes. CDKN2A gene mutations are found in up to 40 percent of familial cases of melanoma, in which multiple family members develop the cancer. These mutations, classified as germline mutations, are typically inherited and are present in essentially all of the body's cells. The CDKN2A gene mutations found in melanoma result in a nonfunctional p16(INK4A) protein. In many cases, a second, somatic mutation occurs in the normal copy of the gene in melanocytes. In about half of melanomas, part or all of the CDKN2A gene is missing (deleted). In many other cases, the CDKN2A gene has a mutation or is turned off (inactive). Somatic mutations in other genes involved in cell growth are also needed for a melanoma to develop. Together, the germline and somatic mutations impair the function of proteins that regulate division and senescence, leading to uncontrolled cell growth and the formation of a melanoma.
Individuals with a CDKN2A gene mutation tend to develop melanoma at an earlier age than those without a mutation in the gene. They also tend to develop other cancers during their lifetime, particularly cancers of the pancreas or lung.More About This Health Condition
Germline mutations affecting the CDKN2A gene are associated with other cancers, including breast cancer and pancreatic cancer. In some families, CDKN2A gene mutations are associated with development of only one type of cancer. In other families, mutations can lead to a cancer predisposition syndrome, which increases the risk of developing multiple types of cancer. CDKN2A gene mutations involved in cancer impair production of functional p16(INK4A) or, less commonly, p14(ARF), which can result in uncontrolled cell growth and tumor formation.
Somatic CDKN2A gene mutations have been found in some people with brain tumors and in children with a blood cancer called acute lymphoblastic leukemia.
Other Names for This Gene
- CDK4 inhibitor p16-INK4
- cell cycle negative regulator beta
- cyclin-dependent kinase 4 inhibitor A
- cyclin-dependent kinase inhibitor 2A
- cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)
- cyclin-dependent kinase inhibitor 2A isoform p12
- cyclin-dependent kinase inhibitor 2A isoform p14ARF
- cyclin-dependent kinase inhibitor 2A isoform p16gamma
- cyclin-dependent kinase inhibitor 2A isoform p16INK4a
- multiple tumor suppressor 1
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
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- Jeck WR, Siebold AP, Sharpless NE. Review: a meta-analysis of GWAS and age-associated diseases. Aging Cell. 2012 Oct;11(5):727-31. doi: 10.1111/j.1474-9726.2012.00871.x. Epub 2012 Aug 30. Citation on PubMed or Free article on PubMed Central
- Lim AM, Do H, Young RJ, Wong SQ, Angel C, Collins M, Takano EA, Corry J, Wiesenfeld D, Kleid S, Sigston E, Lyons B, Fox SB, Rischin D, Dobrovic A, Solomon B. Differential mechanisms of CDKN2A (p16) alteration in oral tongue squamous cell carcinomas and correlation with patient outcome. Int J Cancer. 2014 Aug 15;135(4):887-95. doi: 10.1002/ijc.28727. Epub 2014 Jan 30. Citation on PubMed
- Loyo M, Li RJ, Bettegowda C, Pickering CR, Frederick MJ, Myers JN, Agrawal N. Lessons learned from next-generation sequencing in head and neck cancer. Head Neck. 2013 Mar;35(3):454-63. doi: 10.1002/hed.23100. Epub 2012 Aug 21. Citation on PubMed or Free article on PubMed Central
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- Potrony M, Puig-Butille JA, Aguilera P, Badenas C, Carrera C, Malvehy J, Puig S. 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. J Am Acad Dermatol. 2014 Nov;71(5):888-95. doi: 10.1016/j.jaad.2014.06.036. Epub 2014 Jul 24. Citation on PubMed or Free article on PubMed Central
- Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, Kryukov GV, Lawrence MS, Sougnez C, McKenna A, Shefler E, Ramos AH, Stojanov P, Carter SL, Voet D, Cortes ML, Auclair D, Berger MF, Saksena G, Guiducci C, Onofrio RC, Parkin M, Romkes M, Weissfeld JL, Seethala RR, Wang L, Rangel-Escareno C, Fernandez-Lopez JC, Hidalgo-Miranda A, Melendez-Zajgla J, Winckler W, Ardlie K, Gabriel SB, Meyerson M, Lander ES, Getz G, Golub TR, Garraway LA, Grandis JR. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011 Aug 26;333(6046):1157-60. doi: 10.1126/science.1208130. Epub 2011 Jul 28. Citation on PubMed or Free article on PubMed Central
- Taylor NJ, Mitra N, Goldstein AM, Tucker MA, Avril MF, Azizi E, Bergman W, Bishop DT, Bressac-de Paillerets B, Bruno W, Calista D, Cannon-Albright LA, Cuellar F, Cust AE, Demenais F, Elder DE, Gerdes AM, Ghiorzo P, Grazziotin TC, Hansson J, Harland M, Hayward NK, Hocevar M, Hoiom V, Ingvar C, Landi MT, Landman G, Larre-Borges A, Leachman SA, Mann GJ, Nagore E, Olsson H, Palmer JM, Peric B, Pjanova D, Pritchard A, Puig S, van der Stoep N, Wadt KAW, Whitaker L, Yang XR, Newton Bishop JA, Gruis NA, Kanetsky PA; GenoMEL Study Group. Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families. J Invest Dermatol. 2017 Dec;137(12):2606-2612. doi: 10.1016/j.jid.2017.07.829. Epub 2017 Aug 19. Citation on PubMed or Free article on PubMed Central