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Brief Report
July 2018

Association of Retinoic Acid Receptor β Gene With Onset and Progression of Lichen Sclerosus–Associated Vulvar Squamous Cell Carcinoma

Author Affiliations
  • 1Section of Pathology, Oncology and Experimental Biology, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, via Fossato di Mortara 64/B, 44121 Ferrara, Italy
  • 2Section of Dermatology and Infectious Diseases, Department of Medical Sciences, University of Ferrara, via Savonarola 9, 44121 Ferrara, Italy
  • 3Department of Medical Sciences, University of Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy
  • 4Section of Anatomic Pathology, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara and S. Anna University Hospital Via Aldo Moro, 8, 44124 Cona, Ferrara, Italy
JAMA Dermatol. 2018;154(7):819-823. doi:10.1001/jamadermatol.2018.1373
Key Points

Question  Is the retinoic acid receptor β (RARβ) tumor-suppressor gene involved in the onset and/or progression of lichen sclerosus-associated vulvar squamous cell carcinoma (LS-VSCC)?

Findings  In this case-control study of 80 tissue specimens, RARβ expression was strongly downregulated by promoter methylation in LS-VSCC. The degree of promoter methylation correlated with the severity of LS-VSCC: full promoter methylation of RARβ was associated with LS-VSCC among patients with lymph nodes metastasis at diagnosis who subsequently experienced recurrence.

Meaning  RARβ dysregulation may play a role in the tumorigenic process of LS-VSCC and promoter methylation of RARβ may be used as a clinical prognostic marker in patients with LS-VSCC.

Abstract

Importance  Molecular alterations in lichen sclerosus–associated vulvar squamous cell carcinoma (LS-VSCC) are largely unknown.

Objective  To determine whether the retinoic acid receptor β (RARβ) tumor-suppressor gene is involved in the onset and/or progression of LS-VSCC.

Design, Setting, and Participants  The case-control study, conducted at University-Hospital of Ferrara, Italy, included 20 LS-VSCC (mean [SD] age, 75 [3] years) and 20 cancer-associated vulvar LS (caVLS; mean [SD] age, 62 [11] years) formalin-fixed embedded tissue specimens, 20 cancer-free vulvar LS (cfVLS), and 20 normal skin fresh specimens from diagnostic biopsies and women surgically treated for nonmalignant skin lesions, respectively. RARβ gene expression and promoter methylation were investigated in LS-VSCC and caVLS adjacent to VSCC specimens, and in cfVLS and normal skin specimens, as controls, by RT-Q real-time polymerase chain reaction (PCR) analysis, and sequencing of PCR-amplified bisulfite-treated DNA. c-Jun expression, an RARβ pathway–related gene, was also investigated.

Main Outcomes and Measures  RARβ expression, correlation with its promoter methylation and c-Jun expression, and association with onset or progression of LS-VSCC.

Results  In LS-VSCC, RARβ messenger RNA was 3.4-, 3.6-, and 4.8-fold lower than in caVLS (P = .001), cfVLS (P = .005), and normal skin (P < .001), respectively. The RARβ mRNA levels were similar in caVLS, cfVLS, and normal skin. The RARβ promoter was hypermethylated in 18 (90%) of 20 LS-VSCC, 11 (55%) of 20 cfVLS, 10 (50%) of 20 caVLS, and 5 (25%) of 20 in the normal skin group. The degree of methylation of RARβ promoter was higher in LS-VSCC, ranging from 5 to 9 (full promoter methylation) CpGs methylated, than in caVLS (P = .02), cfVLS (P = .03), or normal skin (P < .001), which was up to 5 CpGs methylated. Importantly, 0 of 8 LS-VSCC with 5 to 6 CpGs methylated and 5 (63%) of 8 LS-VSCC with 7 to 8 CpGs methylated were from patients with lymph node metastasis at diagnosis, respectively, whereas there were 2 of 2 (100%) LS-VSCC samples with 9 CpG methylated from patients with lymph node metastasis at diagnosis and subsequent recurrence. In LS-VSCC c-Jun mRNA was 4.3-, 1.4-, and 2.6-fold higher than in caVLS (P < .001), cfVLS (P = .001), and normal skin (P < .001), respectively. The expression of c-Jun was similar in caVLS, cfVLS, and normal skin.

Conclusions and Relevance  Hypermethylation-induced RARβ down-expression was associated with LS-VSCC and correlates with the upregulation of c-Jun. The degree of methylation of RARβ promoter increased with the malignancy of LS-VSCC. Therefore, RARβ gene dysregulation may play a role in progression of LS-VSCC, and RARβ promoter methylation status may be used as a prognostic marker in clinical treatment of patients with LS-VSCC.

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