Integrated Whole-Exome and Transcriptome Sequencing Indicated Dysregulation of Cholesterol Metabolism in Eyelid Sebaceous Gland Carcinoma

PURPOSE: To identify the molecular background of eyelid sebaceous gland carcinomas (SCs), we conducted the integrated whole-exome sequencing and transcriptome sequencing for eyelid SCs in this study. METHODS: The genetic alterations were studied by whole-exome sequencing, and the messenger RNA expression was studied using Oxford Nanopore Technologies (ONT) in five paired fresh eyelid SC tissues and adjacent normal tissues. Integrated analysis of exome and transcriptomic information was conducted for filtering candidate driver genes. Protein–protein interaction (PPI) network of filtered candidate genes was analyzed by STRING. The protein expression was verified by immunohistochemistry in 29 eyelid SCs and 17 compared normal sebaceous gland tissues. RESULTS: The average numbers of pathogenic somatic single-nucleotide variants (SNVs) and indels in eyelid SCs were 75 and 28, respectively. Tumor protein p53 (TP53), zinc finger protein 750 (ZNF750), filaggrin 2 (FLG2), valosin-containing protein (VCP), and zinc finger protein 717 (ZNF717) were recurrent mutated genes. A mean of 844 differentially expressed genes (DEGs) were upregulated, and 1401 DEGs were downregulated in SC samples. The intersection of DEG-based pathways and mutation-based pathways was mainly involved in microbial infection and inflammation, immunodeficiency, cancer, lipid metabolism, and the other pathways. The intersection of DEGs and mutated genes consisted of 55 genes, of which 15 genes formed a PPI network with 4 clusters. The PPI cluster composed of scavenger receptor class B member 1 (SCARB1), peroxisome proliferator–activated receptor γ (PPARG), peroxisome proliferator–activated receptor γ coactivator 1α (PPARGC1A) was involved in cholesterol metabolism. The expression of SCARB1 protein was found to be increased, whereas that of PPARG protein was decreased in eyelid SCs compared to that in the normal sebaceous glands. CONCLUSIONS: Increased SCARB1 and decreased PPARG indicated that dysregulation of cholesterol metabolism might be involved in carcinogenesis of eyelid SCs. TRANSLATIONAL RELEVANCE: The malfunction in cholesterol metabolism might advance our knowledge of the carcinogenesis of eyelid SCs.