BackgroundLip exposure to carcinogens lead to several disorders, such as actinic cheilitis (AC) and lower lip squamous cell carcinoma (LLSCC). Although several studies have described important pathways in lip carcinogenesis, the comprehension of association of target genes in this process and their association with tumor microenvironment still need to be better understood.MethodsTissue samples of 30 AC and 17 LLSCC cases were included for histopathological analysis, immunohistochemical expression of CD4, CD8, and PD‐L1, and fluorescence in situ hybridization for AURKA, AURKB, TP53, PTEN, CCND1, and MYC. Non‐parametrical tests were done and p < 0.05 was considered significant.ResultsLLSCC patients presented higher amplifications of AURKA and AURKB, deletion of TP53, and PTEN and rearrangements of MYC than AC. AURKA, AURKB, TP53, PTEN, and CCND1 changes were correlated with PD‐L1 expression.ConclusionsAURKA and AURKB amplifications and other gene changes are pointed by their association of lip disorders.