CDKN2A and esophageal squamous cell carcinoma: P16INK4a expression is frequently reduced in ESCC and this is due to various mechanisms, including aberrant p16INK4a gene methylation observed in 62% of cases [44], loss of heterozygosity of the p16INK4a gene observed in 13% of cases [45], mutations of the p16INK4a gene observed in 6% of cases [44].