The meaning of p16^ink4a expression in tumors: Functional significance, clinical associations and future developments

The CDKN2A gene is a tumor suppressor that encodes the CDK4/6 inhibitor p16^ink4a. Loss of this tumor suppressor contributes to the bypass of critical senescent signals and is associated with progression to malignant disease. However, the high-level expression of p16^ink4a in tumors is associated with aggressive subtypes of disease, and in certain clinical settings elevated p16^ink4a expression is an important determinant for disease prognosis and therapeutic response. These seemingly contradictory facets of p16^ink4a expression have lead to confusion related to the meaning of this tumor suppression in tumor pathobiology. As reviewed here, the alternative expression of p16^ink4a represents an ideal marker for considering RB-pathway function, tumor heterogeneity and novel means for directing therapy.