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p53 is a stress-activated tumour suppressor gene, and its mutation has been associated with solid tumours including non-melanoma skin cancers. Sestrin2 expression is associated with DNA damage and oxidative stress and has been described as a downstream target of p53 network. However, its role in sebaceous gland carcinoma (SGC) remains unexplored.To determine the role of p53 and its downstream target gene sestrin2 expression and p53 gene mutation status in SGC.Twenty cases of eyelid SGC tumour and circulating cell-free DNA (ccfDNA) were subjected to mutational analysis of p53 gene. p53 and sesrin2 expression was evaluated by immunohistochemistry. Results were correlated with the clinicopathological features of eyelid SGC.p53 gene mutations was detected in 25% of the SGC cases. A C>T transition was identified in exon 6 in a single patient in both tumour and ccfDNA. A G>T transversion leading to amino acid change D259Y was seen in four patients. A splice site mutation affected a single case in exon 6. p53 expression was observed in 55% SGC. Loss of sestrin2 in 55% SGC cases correlated with poor tumour differentiation (P=0.0001), upper eyelid involvement (P=0.004), p53 mutation (P=0.039) and with mutant p53 expression (P=0.0001).Sestrin2 expression was found to be significantly reduced in p53 mutated SGC cases and in cases with strong p53 nuclear immunopositivity, suggesting that loss of sestrin2 may be of biological significance in the development of SGC and as a key downstream component of p53 tumour suppression network in eyelid SGC.