Friday 12 December 2003
p16 protein, P16, INK4, INK4A, CYCLIN-DEPENDENT KINASE INHIBITOR 2A, CDKN2A
Definition: p16 is an inhibitor of cyclin-dependent kinases. p16INK4 gene encodes a specific inhibitor of cyclin-dependent kinase 4 (CDK4). p16INK4a binds to cyclin D-CDK4 and promotes the inhibitory effects of RB.
Since the CDK4/cyclin D complex propels a cell to go through the G1 check point of the cell cycle, a critical phase of cell division, alteration of the p16INK4 gene could lead a cell to uncontrolled proliferation and malignant transformation.
Mutations of the CDKN2A locus have been found in 20% to 50% of familial melanomas.
Among sporadic tumors, p16INK4a mutations are present in up to 50% of pancreatic adenocarcinomas and squamous cell carcinomas of the esophagus, and have also been detected in bladder, head, and neck tumors and in cholangiocarcinomas.
Mutated alleles of p16INK4a present in these tumors have lost their capacity to block cyclin D-CDK4 activity and to prevent RB phosphorylation during the cell cycle. In some tumors, such as cervical cancer, p16INK4a is frequently inactivated by hypermethylation of the gene, without the presence of a mutation (see discussion of epigenetic changes).
germline mutations in familial atypical multiple mole melanoma (FAMMM) (MIM.155601)
- familial melanoma of the skin in combination with multiple atypical precursor naevi (17492760)
germline mutation in increased risk of
- pancreatic adenocarcinoma
- carcinomas of the pharynx and oral cavity
- head and neck or oral squamous cell carcinomas (OSCC)
- multiple head and neck tumors
CDKN2A somatic deletion
- glioblastoma (31%)
- anaplastic oligodendroglioma
- supratentorial primitive neuroectodermal tumors of the central nervous system (17592618)
- malignant mesothelioma
Overexpression of p16 has been observed in cervical intraepithelial lesions and invasive carcinomas associated with high-risk HPV types.
Most endocervical adenocarcinomas contain high-risk human papillomavirus (HPV) DNA (endometrial adenocarcinomas rarely do).
CDKN2A is frequently and differentially methylated in ependymal tumours. (14636164)
Distinction of endocervical adenocarcinomas and endometrial adenocarcinomas (15043304)
low-grade squamous cervical lesions
p16 and L1 immunohistochemistry can be helpful for estimating the biologic potentiality of low-grade squamous cervical lesions. Particularly in cases in which the grade of the lesion is morphologically difficult to assess, the p16/L1 expression pattern could be useful for planning the clinical management of these women.
RB/E2A pathway (P16(INK4A)-CDK4/6-RB pathway)
p16 FISH deletion in surface epithelial mesothelial proliferations is predictive of underlying invasive mesothelioma. Hwang H, Tse C, Rodriguez S, Gown A, Churg A. Am J Surg Pathol. 2014 May;38(5):681-8. doi : 10.1097/PAS.0000000000000176 PMID: 24503757
Negri G, Bellisano G, Zannoni GF, Rivasi F, Kasal A, Vittadello F, Antoniazzi S, Faa G, Ambu R, Egarter-Vigl E. p16ink4a and HPV L1 Immunohistochemistry is Helpful for Estimating the Behavior of Low-grade Dysplastic Lesions of the Cervix Uteri. Am J Surg Pathol. 2008 Aug 30. PMID: 18769337
Pfister S, Remke M, Toedt G, Werft W, Benner A, Mendrzyk F, Wittmann A, Devens F, von Hoff K, Rutkowski S, Kulozik A, Radlwimmer B, Scheurlen W, Lichter P, Korshunov A. Supratentorial primitive neuroectodermal tumors of the central nervous system frequently harbor deletions of the CDKN2A locus and other genomic aberrations distinct from medulloblastomas. Genes Chromosomes Cancer. 2007 Sep;46(9):839-51. PMID: 17592618
Kannengiesser C, Dalle S, Leccia MT, Avril MF, Bonadona V, Chompret A, Lasset C, Leroux D, Thomas L, Lesueur F, Lenoir G, Sarasin A, Bressac-de Paillerets B. New founder germline mutations of CDKN2A in melanoma-prone families and multiple primary melanoma development in a patient receiving levodopa treatment. Genes Chromosomes Cancer. 2007 Aug;46(8):751-60. PMID: 17492760
Chen Y, Takita J, Mizuguchi M, Tanaka K, Ida K, Koh K, Igarashi T, Hanada R, Tanaka Y, Park MJ, Hayashi Y. Mutation and expression analyses of the MET and CDKN2A genes in rhabdomyosarcoma with emphasis on MET overexpression. Genes Chromosomes Cancer. 2007 Apr;46(4):348-58. PMID: 17243166
Knappskog S, Geisler J, Arnesen T, Lillehaug JR, Lonning PE. A novel type of deletion in the CDKN2A gene identified in a melanoma-prone family. Genes Chromosomes Cancer. 2006 Dec;45(12):1155-63. PMID: 17001621
Kalof AN, Evans MF, Simmons-Arnold L, Beatty BG, Cooper K. p16INK4A Immunoexpression and HPV In Situ Hybridization Signal Patterns: Potential Markers of High-Grade Cervical Intraepithelial Neoplasia. Am J Surg Pathol. 2005 May;29(5):674-9. PMID: 15832093
Maelandsmo GM, Berner JM, Flørenes VA, Forus A, Hovig E, Fodstad O, Myklebost O. Homozygous deletion frequency and expression levels of the CDKN2 gene in human sarcomas—relationship to amplification and mRNA levels of CDK4 and CCND1. Br J Cancer. 1995 Aug;72(2):393-8.PMID: 7640224