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CDKN2A (cyclin dependent kinase 2a / p16)

Written2004-08Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire
Laboratoire de Biochimie Biologie moléculaire, Hôpital Paul Brousse 94800 Villejuif, France
Updated2007-08Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire
Laboratoire de Biochimie Biologie moléculaire, Hôpital Paul Brousse 94800 Villejuif, France

(Note : for Links provided by Atlas : click)


Other aliasCDKN2a
p16- INK4a
LocusID (NCBI) 1029
Atlas_Id 146
Location 9p21.3  [Link to chromosome band 9p21]
Location_base_pair Starts at and ends at bp from pter
  Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics
  CDKN2A (cyclin dependent kinase 2a / p16) Hybridization with Vysis CDKN2A/CEP 9 FISH Probe (Abbott Molecular, US) showing the CDKN2A gene on 9p21.3 (red signals) - Courtesy Adriana Zamecnikova.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ADAMTSL1 (9p22.2) / CDKN2A (9p21.3)CDKN2A (9p21.3) / CDKN2A (9p21.3)CDKN2A (9p21.3) / CDKN2B (9p21.3)
CDKN2A (9p21.3) / CDKN2B-AS1 (9p21.3)CDKN2A (9p21.3) / FAM230A (22q11.21)CDKN2A (9p21.3) / FOCAD (9p21.3)
CDKN2A (9p21.3) / IFNWP19 (9p22)CDKN2A (9p21.3) / MGA (15q15.1)CDKN2A (9p21.3) / MTAP (9p21.3)
CDKN2A (9p21.3) / SRGAP2 (1q32.1)FOCAD (9p21.3) / CDKN2A (9p21.3)GID4 (17p11.2) / CDKN2A (9p21.3)
MGA (15q15.1) / CDKN2A (9p21.3)MTAP (9p21.3) / CDKN2A (9p21.3)STPG1 (1p36.11) / CDKN2A (9p21.3)


Description The gene encompasses 6.6 kb of DNA; 3 exons.
Transcription 471 nucleotides mRNA. The CDKN2 gene generates several transcript variants from different promoters. Each transcript differs in its first exon (E1), and utilizes alternate polyadenylation sites. E1-alpha, which is spliced into the common exons E2 and E3, gives rise to the p16-INK4 transcript. A putative DNA replication origin has been identified in close proximity of INK4/Arf locus that appears to transcriptionally repress p16 in a manner dependent on CDC6.


Description 156 amino acids; 16.5 kDa protein.
Expression Moderately expressed in many organs as thymus, liver, pancreas, prostate, lung, or kidney.
Function P16-INK4a interacts strongly with cyclin-dependent kinase 4 and cyclin-dependent kinase 6 and inhibits their ability to interact with cyclins D. P16-INK4a induces cell cycle arrest at G1 and G2/M checkpoints, blocking them from phosphorylating RB1 and preventing exit from G1 phase of the cell cycle. P16-INK4a could act as a negative regulator of normal cells proliferation.
Homology Belongs to the cdkn2 cyclin-dependent kinase inhibitor family.

Implicated in

Entity Cutaneous malignant melanoma 2 (CMM2)
Disease Malignant melanoma arises de novo or from a preexisting benign nevus, which occurs most often in the skin but also may involve other sites.
Oncogenesis Familial melanoma (comprising between 8 and 12% of all melanoma cases) is a genodermatosis transmitted as an autosomal dominant trait. CDKN2a has been identified as a major susceptibility gene for melanoma. However this gene accounts for a minority of familial melanoma. P16 is functionally inactivated by mutations or deletions, however, because many such mutations occur in exon 2, they can potentially also affect the alternative reading frame (ARF) protein.
Entity Familial atypical multiple mole melanoma carcinoma syndrome (FAMMM)
Disease Patients with the FAMMM syndrome are genetically loaded with an increased risk of developing melanoma and other malignant neoplasms, for example, a pancreatic cancer.
Oncogenesis FAMMM syndrome is an autosomal dominant disorder with variable incomplete penetrance of the clinical phenotypes. Germline mutations in the p16-INK4a gene were found in approximately 40% of the FAMMM syndrome.
Entity Sporadic cancer
Disease Defects in CDKN2a are involved in tumor formation in a wide range of tissues.
Prognosis Aberrant p16 expression is associated with more aggressive behavior.
Oncogenesis LOH on 9p21 is one of the most frequent genetic alterations identified in human cancer. However, point mutations of p16 on the other chromosome are relatively rare. Promoter methylation appears as the commonest mechanism of p16 gene inactivation.
Entity Aging
Note Expression of p16 increases markedly with aging in many human tissues. This finding has led to the proposal that p16 expression could be used as a biomarker of physiologic, as opposed to chronologic, age. It was suggested that an age-induced increase in p16 expression contributes to the decline of replicative potential of certain self-renewing compartments with aging.


Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas.
Bartsch D, Shevlin DW, Tung WS, Kisker O, Wells SA Jr, Goodfellow PJ
Genes, chromosomes & cancer. 1995 ; 14 (3) : 189-195.
PMID 8589035
Frequency of homozygous deletion at p16/CDKN2 in primary human tumours.
Cairns P, Polascik TJ, Eby Y, Tokino K, Califano J, Merlo A, Mao L, Herath J, Jenkins R, Westra W
Nature genetics. 1995 ; 11 (2) : 210-212.
PMID 7550353
Cytogenetic analysis of melanocytes from premalignant nevi and melanomas.
Cowan JM, Halaban R, Francke U
Journal of the National Cancer Institute. 1988 ; 80 (14) : 1159-1164.
PMID 3166071
FAMMM syndrome: pathogenesis and management.
Czajkowski R, Placek W, Drewa G, Czajkowska A, Uchańska G
Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]. 2004 ; 30 (2 Pt 2) : 291-296.
PMID 14871223
The CDKN2A (p16) gene and human cancer.
Foulkes WD, Flanders TY, Pollock PM, Hayward NK
Molecular medicine (Cambridge, Mass.). 1997 ; 3 (1) : 5-20.
PMID 9132280
Oncogenic activity of Cdc6 through repression of the INK4/ARF locus.
Gonzalez S, Klatt P, Delgado S, Conde E, Lopez-Rios F, Sanchez-Cespedes M, Mendez J, Antequera F, Serrano M
Nature. 2006 ; 440 (7084) : 702-706.
PMID 16572177
Germline p16 mutations in familial melanoma.
Hussussian CJ, Struewing JP, Goldstein AM, Higgins PA, Ally DS, Sheahan MD, Clark WH Jr, Tucker MA, Dracopoli NC
Nature genetics. 1994 ; 8 (1) : 15-21.
PMID 7987387
A cell cycle regulator potentially involved in genesis of many tumor types.
Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS 3rd, Johnson BE, Skolnick MH
Science (New York, N.Y.). 1994 ; 264 (5157) : 436-440.
PMID 8153634
Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition.
Koh J, Enders GH, Dynlacht BD, Harlow E
Nature. 1995 ; 375 (6531) : 506-510.
PMID 7777061
Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice.
Krimpenfort P, Quon KC, Mooi WJ, Loonstra A, Berns A
Nature. 2001 ; 413 (6851) : 83-86.
PMID 11544530
p16INK4a induces an age-dependent decline in islet regenerative potential.
Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE
Nature. 2006 ; 443 (7110) : 453-457.
PMID 16957737
Methylation and p16: suppressing the suppressor.
Little M, Wainwright B
Nature medicine. 1995 ; 1 (7) : 633-634.
PMID 7585141
5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers.
Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB, Sidransky D
Nature medicine. 1995 ; 1 (7) : 686-692.
PMID 7585152
Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p16INK4a but not by the alternative reading frame protein p19ARF.
Quelle DE, Cheng M, Ashmun RA, Sherr CJ
Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (2) : 669-673.
PMID 9012842
Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest.
Quelle DE, Zindy F, Ashmun RA, Sherr CJ
Cell. 1995 ; 83 (6) : 993-1000.
PMID 8521522
A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.
Serrano M, Hannon GJ, Beach D
Nature. 1993 ; 366 (6456) : 704-707.
PMID 8259215
Role of the INK4a locus in tumor suppression and cell mortality.
Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA
Cell. 1996 ; 85 (1) : 27-37.
PMID 8620534
The INK4a/ARF locus and melanoma.
Sharpless E, Chin L
Oncogene. 2003 ; 22 (20) : 3092-3098.
PMID 12789286
Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis.
Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW, DePinho RA
Nature. 2001 ; 413 (6851) : 86-91.
PMID 11544531
Complex structure and regulation of the P16 (MTS1) locus.
Stone S, Jiang P, Dayananth P, Tavtigian SV, Katcher H, Parry D, Peters G, Kamb A
Cancer research. 1995 ; 55 (14) : 2988-2994.
PMID 7606716


This paper should be referenced as such :
Saffroy, R ; Lemoine, A ; Debuire, B
CDKN2a (cyclin dependent kinase 2a / p16)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(2):89-90.
Free journal version : [ pdf ]   [ DOI ]
On line version :
History of this paper:
Saffroy, R ; Lemoine, A ; Debuire, B. CDKN2a (cyclin dependent kinase 2a / p16). Atlas Genet Cytogenet Oncol Haematol. 2004;8(4):280-281.

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 33 ]
  del(9p) in Acute Lymphoblastic Leukemia
Follicular Dendritic Cell Sarcoma
Pediatric T-Cell Acute Lymphoblastic Leukemia
t(2;9)(p11;p21) CDKN2A/IGK
t(9;9)(p21;p21) CDKN2A/IFNWP19
t(9;9)(p21;p21) CDKN2A/MTAP
t(9;14)(p21;q11) CDKN2A/TRA
t(9;14)(p21;q11) TRA/CDKN2A
9p Rearrangements in ALL
Acute Lymphoblastic Leukemia with Hypereosinophilia
Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)
Burkitt's lymphoma (BL)
Chronic myelogenous leukaemia (CML)
del(5)(q32q33) EBF1/PDGFRB
del(9p) in Acute Lymphoblastic Leukemia
dic(9;12)(p13;p13) PAX5/ETV6
Primary cutaneous DLBCL, leg type
Follicular Dendritic Cell Sarcoma
Follicular lymphoma (FL)
Nasal T cell lymphoma (published in 2008)
Pediatric T-Cell Acute Lymphoblastic Leukemia
t(3;5)(q25;q34) NPM1/MLF1
t(5;9)(q35;q34) SQSTM1/NUP214
t(6;14)(p22;q32) IGH/ID4
t(7;12)(q34;p13) TRB/CCND2::t(12;14)(p13;q11) TRA or TRD/CCND2
t(9;14)(q34;q32) EML1/ABL1
T-lineage acute lymphoblastic leukemia (T-ALL)
Classification of T-Cell disorders
t(2;9)(p11;p21) CDKN2A/IGK
t(9;9)(p21;p21) CDKN2A/IFNWP19
t(9;9)(p21;p21) CDKN2A/MTAP
t(9;14)(p21;q11) CDKN2A/TRA
t(9;14)(p21;q11) TRA/CDKN2A

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 47 ]
  Head and Neck: Odontogenic tumor: Ameloblastoma
Nervous system: Astrocytic tumors
Esophagus: Barrett's esophagus, dysplasia and adenocarcinoma
Bladder: Squamous cell carcinoma
Bladder: Urothelial carcinomas
Neuro-Endocrine/Endocrine system: Carcinoid tumors
Bone: Chordoma
Bone: Conventional Osteosarcoma
Nervous system: Ependymomas
Gallbladder: Carcinoma of the gallbladder and extrahepatic bile ducts
Nervous System: Glioma: an overview
Head and Neck: Squamous cell carcinoma: an overview
Head and Neck: Epidermoid carcinoma
Liver: Hepatocellular carcinoma
Gallbladder: Intrahepatic cholangiocarcinoma
Head and Neck: Laryngeal tumors: an overview
Head and Neck: Laryngeal squamous cell carcinoma
Liver tumors: an overview
Lung: Non-small cell carcinoma
Lung: small cell cancer
Male breast cancer
Testis: Germ cell tumors
Nervous system: Meningioma
Malignant Mesothelioma
Head and Neck: Oral leukoplakia
Head and Neck: Oral squamous cell carcinoma
Bone: Osteochondroma
Bone: Osteosarcoma
Ovarian tumours : an overview
Ovary: Epithelial tumors
Pancreatic tumors: an overview
Penile tumors: an overview
Nervous system: Peripheral nerve sheath tumors
Eye: Retinoma
Head and Neck: Salivary gland tumors: an overview
Skin: Melanoma
Soft tissue tumors: an overview
Squamous cell cancer
Lung: Translocations in Squamous Cell Carcinoma
t(1;9)(q32;p21) CDKN2A/SRGAP2
MTAP/CDKN2A (9p21)
t(9;15)(p21;q15) CDKN2A/MGA
t(9;15)(p21;q15) MGA/CDKN2A
Uterus Tumours: an Overview
Eye: Posterior uveal melanoma

Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 4 ]
  Dysplastic nevus syndrome (DNS) Familial melanoma Hereditary pancreatic cancer Melanoma-Astrocytoma syndrome

External links

Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)1029
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
canSAR (ICR) (select the gene name)
Other database
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Thu Oct 18 17:31:35 CEST 2018

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