# Histological and Genetic Markers of Cellular Senescence in Keratinocyte Cancers and Actinic Keratosis: A Systematic Review

## TL;DR

This review explores how cellular senescence markers differ in skin cancers and precancerous lesions, highlighting potential targets for treatment.

## Contribution

The study systematically reviews histological and genetic markers of senescence in keratinocyte cancers and actinic keratosis.

## Key findings

- Actinic keratosis shows high p21CIP1 and gamma-H2AX expression, indicating early senescence.
- Invasive cSCC shows reduced p21CIP1 and p53, with p16INK4a accumulation despite lack of cell arrest.
- TERT promoter mutations are common in cSCC and BCC but rare in actinic keratosis.

## Abstract

Cellular senescence is a stress-induced cell-cycle arrest that constrains expansion of ultraviolet-damaged keratinocytes yet can remodel the microenvironment. This systematic review evaluated histological and genetic or epigenetic senescence markers in actinic keratosis (AK), cutaneous squamous cell carcinoma (cSCC), and basal cell carcinoma (BCC). PubMed, Scopus, and Web of Science were searched (January 2005–May 2025); 34 human studies were included. AK showed an early senescent signature with frequent cyclin-dependent kinase inhibitor p21 (p21CIP1) expression (82.1%) and DNA damage signaling, including phosphorylated histone H2AX (gamma-H2AX) positivity (77%). In invasive cSCC, p21CIP1 fell to 43.9% and tumor suppressor p53 immunoreactivity often declined, whereas cyclin-dependent kinase inhibitor p16 (p16INK4a) commonly accumulated without arrest, including cytoplasmic staining at invasion fronts. Reported escape pathways involved c-Jun N-terminal kinase 2 activity and long noncoding RNA PVT1–dependent repression of p21. Telomerase reverse transcriptase (TERT) promoter mutations were prevalent in cSCC (about 50%) and BCC (up to 78%) but uncommon in AK, consistent with late telomerase activation. Study heterogeneity, variable antibody scoring, and limited assessment of senescence-associated beta-galactosidase and secretory mediators restricted cross-study comparability. Standardized, spatially resolved profiling may refine risk stratification and support senescence-targeted prevention and therapy in keratinocyte cancers.