CDKN2A encodes P16-INK4a, a protein that interacts strongly with cyclin-dependent kinase (CDK)4 and CDK6 and inhibits their ability to interact with cyclins D. P16-INK4a is capable of inducing cell cycle arrest in G1 and G2 phases. It acts as a tumor suppressor.
CDKN2A is one of the most frequently alterered genes in tumors. Somatic deletions and/or mutations of various types have been observed in tumors of the following tissues (among others): genital tract, pleura, pancreas, biliary tract, skin, upper aerodigestive tract, CNS, oesophagus, urinary tract…Somatic mutations have been found throughout the gene.
Among skin tumors, CDKN2A alterations are highly associated with cutaneous melanoma (while they are rare in uveal melanoma) and several melanoma-associated syndromes, such as:
- Cutaneous malignant melanoma type 2 (CMM2). This syndrome arises de novo or from a pre-existing benign nevus, which occurs most often in the skin but also may involve other sites. CMM2 is transmitted as an autosomal dominant trait.
- Familial atypical multiple mole melanoma carcinoma syndrome (FAMMM), in which patients have an increased risk of developing melanoma and other malignant neoplasms, for example, a pancreatic cancer (FAMMMPC). Germline CDKN2A mutations arefound in approximately 40% of the FAMMM syndrome patients.
- Melanoma-astrocytoma syndrome, which is characterized by a dual predisposition to melanoma and neural system tumors, commonly astrocytoma.
Genetic defects in CDKN2A may also be a cause of Li-Fraumeni syndrome (LFS). LFS is a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53.
References (open access):
Main roads to melanoma. Palmieri G, Capone M, Ascierto ML, Gentilcore G, Stroncek DF, Casula M, Sini MC, Palla M, Mozzillo N, Ascierto PA. J Transl Med. 2009 Oct 14;7:86.
The contribution of large genomic deletions at the CDKN2A locus to the burden of familial melanoma. Lesueur F, de Lichy M, Barrois M, Durand G, Bombled J, Avril MF, Chompret A, Boitier F, Lenoir GM; French Familial Melanoma Study Group, Bressac-de Paillerets B, Baccard M, Bachollet B, Berthet P, Bonadona V, Bonnetblanc JM, Caron O, Chevrant-Breton J, Cuny JF, Dalle S, Delaunay M, Demange L, De Quatrebarbes J, Doré JF, Frénay M, Fricker JP, Gauthier-Villars M, Gesta P, Giraud S, Gorry P, Grange F, Green A, Huiart L, Janin N, Joly P, Kérob D, Lasset C, Leroux D, Limacher JM, Longy M, Mansard S, Marrou K, Martin-Denavit T, Mateus C, Maubec E, Olivier-Faivre L, Orlandini V, Pujol P, Sassolas B, Stoppa-Lyonnet D, Thomas L, Vabres P, Venat L, Wierzbicka E, Zattara H. Br J Cancer. 2008 Jul 22;99(2):364-70.