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

Abstract

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.

Lipid droplets provide metabolic flexibility for cancer progression

“…In eukaryotic cells, intracellular lipids are collected, stored, and supplied to different fates in a timely manner by atypical organelles called lipid droplets (LDs) [18]. Transformed cells often accumulate LDs, a phenotype increasingly recognized as a new hallmark of cancer cells, reflecting a highly dynamic lipid metabolism [19,20] (Fig. 1).…”

“…Diabetic patients are more susceptible to developing colorectal, pancreatic, gallbladder, biliary, hepatocellular, gastric, esophageal, oral, breast, endometrial, ovary, kidney, and thyroid cancers as well as leukemias [93]. Indeed, whilst alteration in lipid metabolism could have a direct or indirect role in oncogenicity in cancers such as liposarcoma [94], sebaceous gland carcinoma [20], and hepatocellular carcinoma [95], it is increasingly considered as a risk factor for many other cancer types [96,97]. For instance, LDs correlate negatively with tumor grade and differentiation status in liposarcoma: they are prominently present in dedifferentiated liposarcomas and absent in well-differentiated liposarcomas, lipomas, and normal adipose tissue [98].…”

The effectiveness and safety of eyelid defect reconstruction after sebaceous carcinoma of the eyelid surgery: A protocol for systematic review and meta-analysis

“…[2,16] The effective excisional surgery involves wide local excision and frozen sectioning or Mohs micrographic surgery. [17][18][19][20][21][22] Both therapies reduce recurrence, metastasis, and tumor-related mortality by 15.9%, 12.1%, and 6.2%, respectively. [23] Postoperative reconstruction is performed to maintain eyelid function and aesthetics.…”

Base-Excision Repair Mutational Signature in Two Sebaceous Carcinomas of the Eyelid

“…The molecular profile of cutaneous malignant adnexal carcinomas has only been partially explored. Molecular analyses, including next-generation sequencing, have been conducted on small cohorts, examining targeted gene panels and/or whole exome sequencing [9][10][11][12][13]. Depending on the study, periocular SGC has been classified into three or two clinical entities.…”