CDKN2A is known to be a classic tumor suppressor gene. The gene codes for a protein, p16, which is an inhibitor of cyclin dependent kinases, and thus, acts as a negative regulator of cell proliferation. p16 interacts strongly with cyclin-dependent kinases 4 and 6 and inhibits their ability to interact with cyclins D, blocking them from phosphorylating the retinoblastoma protein (RB1). This induces cell cycle arrest at G1 and G2/M checkpoints, and prevents exit from G1 phase of the cell cycle. Mutations in the gene cause the protein to lose their capacity to block the Cyclin D/CDK4 activation, resulting in uncontrolled cell proliferations, and development of malignancies. Apart from mutations, hypermethylation of the gene has also been shown to cause inactivation in some cancers. A splice variant of the gene, p14/ARF plays its part in regulating cell proliferation by sequestering the p53 binding protein MDM2 in the nucleolus, and thereby accumulating p53, which is followed by p53 mediated apoptosis of the cell.
Mutations in this locus have been found in familial melanomas (20%), and familial atypical multiple mole melanoma carcinoma syndrome (40%). Among sporadic tumors, p16/INK4A 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.
The CDKN2A gene, is located on chromosome 9p21, and encompasses 6.6 kb of DNA with three exons. The gene generates at least three different transcript variants from different promoters. Each transcript differs in its 5-prime exon (E1), and utilizes alternate polyadenylation sites. E1-alpha, which is spliced into the common exons E2 and E3, gives rise to the p16/INK4A transcript, the protein product of which has 156 amino acids; with a molecular weight of 16.5 KDa. The p14/ARF protein is a highly arginine enriched, 173 amino acid long protein.
Eissa et al. (2000) examined 168 tumor tissue, 20 schistosomal tissue, and 50 normal tissue samples were examined for the status of the p16 gene by the polymerase chain reaction and by sequencing the DNA fragments produced during PCR. In addition, the expression of p16 protein was examined by Western blot analysis. Deletion of the p16 gene was observed in 72 bladder tumors. Twenty eight of the 72 cases that exhibited p16 deletions also displayed deletions of p15. Only eight cases showed loss of the p15 gene while retaining p16 gene, and p16 deletion with apparently intact p15 gene was identified in 44 cases. Eissa et al. (2000) indicated that deletion in the two genes are associated with low-stage, low grade bladder cancer, schistosomiasis-associated bladder cancer (SABC) and squamous cell carcinoma type (SCC). The expression of p16 protein was undetectable in 75 bladder tumors by Western blot analysis.
Mekawy et al. (2002) studied the incidence of p16/INK4A gene deletions in 30 patients with T-cell acute lymphoblastic leukemia (T-ALL). Clinical examination of the patients was followed by laboratory investigation, involving complete hemogram, bone marrow aspiration and examination, flow cytometric studies for B and T cell precursor markers, and PCR using primers specific for the p16 gene. Results showed a high degree of deletions in the p16 genes (40%), indicating it to be the major target of deletions on 9p21 in T-ALL. Follow-up of the patients showed a complete remission (CR) rate of 63.6% in patients with no deletions, in comparison to 75% CR in patients with deletions in P16 gene.
Eissa et al. (2004) evaluated p16 gene deletion in bladder carcinoma among Egyptian patients, in relation to different clinicopathological features of the tumors and presence or absence of bilharziasis. Tissue specimens were obtained from 132 patients with bladder carcinoma and 50 normal tissue samples from the same patients served as control. In all normal samples, p16 gene was detected. P16 gene was deleted in 38.7% (41/106) of bladder tumors. The deletion of both p16 and p15 genes was associated with poor differentiation grade and presence of bilharziasis. P16 deletion was also correlated to advancing tumor stage. Moreover, p16 and p15 gene deletion was related to tumor progression and might have a role in bilharzial bladder carcinogenesis.
Yakobson et al. (2003) found the val59-to-gly mutation in the CDKN2A gene in a family of Moroccan Jewish ancestry. The impact of the Val59Gly substitution on the function of the cyclin-dependent kinase inhibitor p16(INK4a), a product of the CDKN2A gene, was assessed by protein-protein interaction and cell proliferation assays and related to potential structural alterations predicted by molecular modeling. Seven microsatellite markers in the vicinity of the CDKN2A gene were used to determine whether the mutation in other affected families is identical by descent, or represents a mutational hotspot in the CDKN2A gene. Yakobson et al. (2003) demonstrated that the Val59Gly substitution impairs p16(INK4a) function, and this dysfunction is consistent with structural predictions. A common haplotype of microsatellite markers has been demonstrated for mutation carriers in all pedigrees. This is suggestive for the Val59Gly mutation to be a major contributor to melanoma risk in the families under study and that it may have derived from a single ancestral founder of Mediterranean (possibly Jewish) origin.
Wakil et al. (2016) sought to identify gene loci associated with Coronary Artery Disease (CAD)/Myocardial Infarction (MI) in the Saudi Arabian population. A total of 2668 cases and 3000 controls were recruited to the genome wide association study. Several SNPs linked to CAD/MI were identified in this study. However, the CDKN2A/B gene exhibited the most conspicuous association. The SNP rs10738607_G was significantly associated with CAD [p=2.17E-08, OR=0.78(0.71-0.85)]. Two other SNPs in the CDKN2A/B gene, rs10757274_G and rs1333045_C showed a statistically significant association with MI [p=2.98E-08, OR=0.79(0.73-0.86) and p=1.15E-08, OR=0.79(0.73-0.86)]. These results replicated earlier published studies on European and South Asian populations. The 9p21 locus has previously been implicated in CAD/MI, type II diabetes mellitus, metabolic syndrome and arrhythmic cardiac death in different ethnic groups. This study thus confirmed the association of this gene with CAD/MI in Arab populations.
Yakobson et al. (2003) found the val59-to-gly mutation in the CDKN2A gene in a family of Tunisian Jewish ancestry. [See also: Morocco > Yakobson et al., 2003].