Abstract
Simple SummaryVulvar squamous cell carcinoma (VSCC) is the most common form of vulvar malignancy, and its incidence has increased in recent years. For better diagnosis and prognostication, and to expand available treatment options, molecular characterization of VSCC is crucial. We sought to identify aberrations in DNA methylation in VSCC, as this has been implicated in the development of several cancers. To this end, we performed genome-wide methylation sequencing on a set of VSCC and normal vulvar tissue using the Infinium MethylationEPIC BeadChip array. We detected 199 genes to be differentially methylated in VSCC compared to normal vulvar tissue. Of these, 194 genes were hyper-methylated, which leads to a loss of function of the genes. As most of these genes are involved in transcription regulator activity, our results suggest that disruption of this process plays an important role in VSCC development.DNA methylation is the most widely studied mechanism of epigenetic modification, which can influence gene expression without alterations in DNA sequences. Aberrations in DNA methylation are known to play a role in carcinogenesis, and methylation profiling has enabled the identification of biomarkers of potential clinical interest for several cancers. For vulvar squamous cell carcinoma (VSCC), however, methylation profiling remains an under-studied area. We sought to identify differentially methylated genes (DMGs) in VSCC, by performing Infinium MethylationEPIC BeadChip (Illumina) array sequencing, on a set of primary VSCC (n = 18), and normal vulvar tissue from women with no history of vulvar (pre)malignancies (n = 6). Using a false-discovery rate of 0.05, beta-difference (Δβ) of ±0.5, and CpG-island probes as cut-offs, 199 DMGs (195 hyper-methylated, 4 hypo-methylated) were identified for VSCC. Most of the hyper-methylated genes were found to be involved in transcription regulator activity, indicating that disruption of this process plays a vital role in VSCC development. The majority of VSCCs harbored amplifications of chromosomes 3, 8, and 9. We identified a set of DMGs in this exploratory, hypothesis-generating study, which we hope will facilitate epigenetic profiling of VSCCs. Prognostic relevance of these DMGs deserves further exploration in larger cohorts of VSCC and its precursor lesions.
Highlights
Vulvar squamous cell carcinoma (VSCC) is considered to be a rare cancer; an increase in the incidence and a decrease in the median age of onset has been witnessed over recent decades [1,2,3,4]
We aimed to identify methylation-based biomarkers of potential clinical relevance by investigating the genes that are differentially methylated in VSCC compared to normal vulvar tissue
We identified a set of 199 differentially methylated genes (DMGs) for VSCC; of these, the majority (n = 194) were hyper-methylated; hypermethylation is considered to down-regulate gene expression
Summary
Vulvar squamous cell carcinoma (VSCC) is considered to be a rare cancer; an increase in the incidence and a decrease in the median age of onset has been witnessed over recent decades [1,2,3,4]. VSCC comprises two main etiological subtypes–human papillomavirus (HPV)-associated and HPV-independent [5,6]. These subtypes are known to differ in their epidemiological, clinical, pathological, and molecular characteristics. HPV-associated VSCC, the less prevalent subtype, affects women of 50–60 years of age, and is associated with a favorable prognosis [7,8]. The more prevalent HPVindependent VSCC usually develops on the background of chronic dermatoses in women of >70 years of age, and is associated with high rates of recurrence [2,5,6,7,9]. Recent studies have discovered molecular heterogeneity among HPV-independent VSCCs, as some of these tumors can be TP53 wild-type, and harbor HRAS or NOTCH1 mutations instead [7,10]
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