title: Distinct pathways in the pathogenesis of sebaceous carcinomas implicated by differentially expressed microRNAs.
abstract: OBJECTIVE
  The molecular-genetic alterations contributing to the pathogenesis of sebaceous carcinoma and sebaceous adenoma remain poorly understood. Given that sebaceous carcinoma is associated with substantial morbidity and mortality, there is a critical need to delineate the pathways driving sebaceous carcinoma and candidate molecules for targeted therapy.
  
  
  OBJECTIVE
  To describe differentially expressed microRNAs (miRNAs) in a series of periocular sebaceous carcinomas compared with sebaceous adenomas in order to identify pathways driving the pathogenesis of sebaceous carcinoma.
  
  
  METHODS
  Thirty sebaceous carcinomas and 23 sebaceous adenomas (including 11 that were confirmed to be related to Muir-Torre syndrome and 6 that were confirmed to be sporadic) were obtained from archives (from 48 patients) of 2 institutions (University of Texas MD Anderson Cancer Center, Houston, and Siriraj Hospital, Mahidol University, Bangkok, Thailand) and profiled.
  
  
  METHODS
  Expression of miRNAs was determined using total RNA from formalin-fixed, paraffin-embedded tissue and real-time reverse transcription-polymerase chain reaction performed in a microfluidics card containing 378 unique miRNAs. Fold change was determined using the ΔΔCt method (reference probe, RNU48). Median centering was used to normalize the data. Two-sample t tests were used to identify differentially expressed miRNAs. The false discovery rate was assessed by β-uniform mixture analysis of P values from the t statistics. Significance was defined by this estimated false discovery rate.
  
  
  RESULTS
  Serial testing and validation confirmed overexpression of 2 miRNAs previously reported to be oncogenic, miR-486-5p (4.4-fold; P = 2.4 × 10-8) and miR-184 (3.5-fold; P = 1.7 × 10-6), in sebaceous carcinoma compared with sebaceous adenoma and downregulation of 2 miRNAs previously reported to have tumor-suppressive properties, miR-211 (-5.8-fold; P = 2.3 × 10-9) and miR-518d (-4.5-fold; 6.7 × 10-5), in sebaceous carcinoma compared with sebaceous adenoma.
  
  
  CONCLUSIONS
  Sebaceous carcinoma exhibits an miRNA expression profile distinct from that of sebaceous adenoma, implicating dysregulation of NF-κB and PTEN (targets of miR-486-5p) and TGF-β signaling (target of miR-211) in the pathogenesis of sebaceous carcinoma. The identification of miRNAs whose expression is altered in sebaceous carcinoma compared with sebaceous adenoma provides a novel entry point for a more comprehensive understanding of the molecular-genetic alterations pivotal to the development of sebaceous carcinoma.
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Tetzlaff
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Curry
authors.affiliation: Orbital Oncology and Ophthalmic Plastic Surgery, Department of Plastic Surgery, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Vivian
authors.initials: V
authors.lastname: Yin
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston3Department of Dermatology, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Penvadee
authors.initials: P
authors.lastname: Pattanaprichakul
authors.affiliation: Department of Dermatology, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Jane
authors.initials: J
authors.lastname: Manonukul
authors.affiliation: Department of Dermatology, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Mongkol
authors.initials: M
authors.lastname: Uiprasertkul
authors.affiliation: Department of Biostatistics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Ganiraju C
authors.initials: GC
authors.lastname: Manyam
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Khalida M
authors.initials: KM
authors.lastname: Wani
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
authors.affiliation: Department of Biostatistics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Victor G
authors.initials: VG
authors.lastname: Prieto
authors.affiliation: Orbital Oncology and Ophthalmic Plastic Surgery, Department of Plastic Surgery, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Bita
authors.initials: B
authors.lastname: Esmaeli
mesh_terms: D018266:Adenocarcinoma, Sebaceous / Q000235:genetics* / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005142:Eyelid Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008207:Lymphatic Metastasis; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D055653:Muir-Torre Syndrome / Q000235:genetics* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C534424:MIRN184 microRNA, human; C552722:MIRN195 microRNA, human; C549405:MIRN211 microRNA, human; C560945:MIRN486 microRNA, human; D035683:MicroRNAs