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- Title
Hypermethylation-Induced Inactivation of the IRF6 Gene as a Possible Early Event in Progression of Vulvar Squamous Cell Carcinoma Associated With Lichen Sclerosus.
- Authors
Rotondo, John Charles; Borghi, Alessandro; Selvatici, Rita; Magri, Eros; Bianchini, Enzo; Montinari, Elena; Corazza, Monica; Virgili, Annarosa; Tognon, Mauro; Martini, Fernanda
- Abstract
<bold>Importance: </bold>The molecular mechanism leading to the development of vulvar squamous cell carcinoma (VSCC) from vulvar lichen sclerosus (VLS) is unknown.<bold>Objective: </bold>To assess the possible involvement of the IRF6 tumor-suppressor gene in the development of VSCC from VLS.<bold>Design: </bold>In laboratories at the University of Ferrara, Ferrara, Italy, IRF6 gene expression and promoter methylation were investigated in paraffin-embedded VSCC and adjacent vulvar intraepithelial neoplasia (VIN) and VLS specimens, in cancer-free VLS (cfVLS) specimens, and in healthy skin specimens by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) analysis and by sequencing of PCR-amplified bisulfite-treated DNA. Methylation-induced dysregulation was assessed by expression of p63, the IRF6-transactivator gene.<bold>Main Outcomes and Measures: </bold>IRF6 expression, correlation with promoter methylation and p63 expression, and association with development of VSCC from VLS.<bold>Results: </bold>Specimens from 60 participating women (1 specimen from each) were analyzed for the study (mean [SD] age, 66.3 [12.1] years): 20 paraffin-embedded specimens of VSCC (patient age, 75.3 [8.3] years) with adjacent VLS lesions, in 5 of which VIN preneoplastic tissue was also present (patient age, 64.3 [15.3] years); 20 cfVLS specimens (patient age, 62.1 [11.4] years) obtained from diagnostic biopsies; and 20 normal skin specimens from noncancer surgical patients (patient age, 61.4 [9.1] years). IRF6 messenger RNA was found to be reduced 4.5-, 2.9-, 6.6-, and 2.2-fold in VLS, VIN, VSCC, and cfVLS specimens, respectively, compared with controls, although p63 was still expressed in all specimens. IRF6 promoter was hypermethylated in 9 (45%) of 20 VLS specimens, 1 (20%) of 5 VIN specimens, 16 (80%) of 20 VSCC specimens, 2 (10%) of 20 cfVLS specimens, and 0 normal skin specimens.<bold>Conclusions and Relevance: </bold>IRF6 dysregulation may be involved in the development of VSCC from VLS. Methylation of the IRF6 promoter may be a marker of cancer risk in patients with VLS.
- Subjects
RNA analysis; GENE expression; GENES; PROTEINS; SKIN; SQUAMOUS cell carcinoma; TRANSCRIPTION factors; VULVAR tumors; CARCINOMA in situ; DNA methylation; LICHEN sclerosus et atrophicus; NEOPLASTIC cell transformation
- Publication
JAMA Dermatology, 2016, Vol 152, Issue 8, p928
- ISSN
2168-6068
- Publication type
journal article
- DOI
10.1001/jamadermatol.2016.1336