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Original Investigation |

Distinct Pathways in the Pathogenesis of Sebaceous Carcinomas Implicated by Differentially Expressed MicroRNAs

Michael T. Tetzlaff, MD, PhD1; Jonathan L. Curry, MD1; Vivian Yin, MD2; Penvadee Pattanaprichakul, MD1,3; Jane Manonukul, MD3; Mongkol Uiprasertkul, MD3; Ganiraju C. Manyam, MS4; Khalida M. Wani, PhD1; Kenneth Aldape, MD, PhD1; Li Zhang, PhD4; Victor G. Prieto, MD, PhD1; Bita Esmaeli, MD2
[+] Author Affiliations
1Department of Pathology, University of Texas MD Anderson Cancer Center, Houston
2Orbital Oncology and Ophthalmic Plastic Surgery, Department of Plastic Surgery, University of Texas MD Anderson Cancer Center, Houston
3Department of Dermatology, Siriraj Hospital, Mahidol University, Bangkok, Thailand
4Department of Biostatistics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston
JAMA Ophthalmol. 2015;133(10):1109-1116. doi:10.1001/jamaophthalmol.2015.2310.
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Importance  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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 and Relevance  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.

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Figure 1.
Unsupervised Hierarchical Clustering Analysis of Sebaceous Neoplasms According to All MicroRNAs (miRNAs) Profiled
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Figure 2.
Supervised Hierarchical Clustering Analysis of Sebaceous Neoplasms According to MicroRNAs (miRNAs) With Significantly Different Expression

Selected miRNAs were derived after application of a minimum threshold of a false discovery rate of less than 0.01 and a fold change of 2.0 or greater.

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Figure 3.
miR-486-5p Upregulated in Sebaceous Carcinoma

A, Dot plot shows miR-486-5p expression in sebaceous carcinomas and adenomas. B, Benign sebaceous gland (hematoxylin-eosin, original magnification ×200). C, In situ hybridization of miR-486-5p in benign sebaceous glands (original magnification ×400) (inset, negative control [original magnification ×400]). D, Invasive sebaceous carcinoma of the eyelid (hematoxylin-eosin, original magnification ×200) (inset, cytoplasmic vacuoles confirm sebaceous differentiation [original magnification ×400]). E, In situ hybridization of miR-486-5p in sebaceous carcinoma (original magnification ×400) (inset, negative control [original magnification ×400]).

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