[5][6][7] p16 can be used as a biomarker to improve the histological diagnostic accuracy of grade 3 cervical intraepithelial neoplasia (CIN).

[12] This reduction in the division and production of stem cells protects against cancer while increasing the risks associated with cellular senescence.

[13][14] This pathway connects the processes of tumor oncogenesis and senescence, fixing them on opposite ends of a spectrum.

Conversely, activation of p16 through reactive oxygen species, DNA damage, or senescence leads to the buildup of p16 in tissues and is implicated in the aging of cells.

Tissue samples of primary oral squamous cell carcinoma (OSCC) often display hypermethylation in the promoter regions of p16.

Cancer cells show a significant increase in the accumulation of methylation in CpG islands in the promoter region of p16.

Both mechanisms cause the same end result: downregulation of gene expression that leads to decreased levels of the p16 protein.

For patients with oropharyngeal squamous cell carcinoma, using immunohistochemistry to detect the presence of the p16 biomarker has been shown to be the strongest indicator of disease course.

[35][36][37] p16 deletion detected by FISH in surface epithelial mesothelial proliferations is predictive of underlying invasive mesothelioma.

p16 immunohistochemical expression alone cannot be used to discriminate between SCCs arising from uterine cervix versus urinary bladder.

[42] Therefore, p16INK4a could potentially be used as a blood test that measures how fast the body's tissues are aging at a molecular level.

[46] However, recently, it has been demonstrated that p16INK4a protects from depletion after a powerful proneurogenic stimulus—i.e., running— also stem and progenitor cells of the aged dentate gyrus.

[47] Therefore, p16Ink4a plays a role in the maintenance of dentate gyrus stem cells after stimulus, by keeping a reserve of their self-renewal capacity during aging.

Since the dentate gyrus plays a key role in spatial and contextual memory formation, p16INK4a is implicated in the maintenance of cognitive functions during aging.

Researchers Manuel Serrano, Gregory J. Hannon and David Beach discovered p16 in 1993 and correctly characterized the protein as a cyclin-dependent kinase inhibitor.

The protein was suspected to be involved in carcinogenesis due to the observation that mutation or deletion in the gene was implicated in human cancer cell lines.