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)?
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.
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.
Molecular alterations in lichen sclerosus–associated vulvar squamous cell carcinoma (LS-VSCC) are largely unknown.
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  years) and 20 cancer-associated vulvar LS (caVLS; mean [SD] age, 62  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.
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.
Rotondo JC, Borghi A, Selvatici R, et al. Association of Retinoic Acid Receptor β Gene With Onset and Progression of Lichen Sclerosus–Associated Vulvar Squamous Cell Carcinoma. JAMA Dermatol. 2018;154(7):819–823. doi:10.1001/jamadermatol.2018.1373
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