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.

Pathology

Mutations of this locus have been found in about 20% 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) (melanoma of the skin in combination with multiple atypical precursor naevi

 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
• melanoma

 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).

Diagnosis use

 Distinction of endocervical adenocarcinomas and endometrial adenocarcinomas (#15043304#)

See also

 ARF (p14ARF)
 RB/E2A pathway (P16(INK4A)-CDK4/6-RB pathway)

References

 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#

 Weitzman JB. p16(Ink4a) and p19(Arf): terrible twins. Trends Mol Med. 2001 Nov;7(11):489. PMID: #11689318#