DNA methylation markers for cancer risk prediction of vulvar intraepithelial neoplasia

Superficially, invasive vulvar squamous cell carcinoma (SISCCA) (FIGO stage IA) is a rare subset of vulvar cancer defined as a single lesion measuring ≤2 cm with a depth of invasion of ≤1.0 mm. This is a retrospective study performed on 48 patients with SISCCA, surgically treated between 1981 and 2018 at the S. Anna Hospital, University of Turin, to evaluate pathological characteristics and prognosis of these tumors. Ten patients (21%) recurred: seven (14%) as SISCCA and three (7%) as deeply invasive carcinoma. One case with perineural invasion and groin node metastasis at recurrence. No patient had groin lymph node metastases at initial diagnosis. Site of SISCCA, type of surgery, status of surgical margins, and histopathological features did not differ between recurrent and non-recurrent patients. We observed a non-significant trend towards an increase of recurrences in younger women (median age: 63 years vs. 70 years, p = 0.09), while, surprisingly, smaller tumors (<12 mm) were significantly related to tumor relapse (p = 0.03). Overall, SISCCA has a good long-term prognosis, regardless of the pathological characteristics and the type of surgical treatment. We recommend close follow-up, especially for younger patients and for small tumors, due to the possibility of recurrence or re-occurrence even after years.

Section: Discussionsupporting

confidence: 53%

Superficially Invasive Vulvar Squamous Cell Carcinoma: A 37-Year-Long Experience of a Tertiary Referral Center

Preti

Borella

Gallio

et al. 2021

“…DNA methylation signatures have emerged as promising biomarkers in oncology capable of measuring risk factor exposure [ 35 , 46 , 47 ], discriminating different types of primary tumors [ 48 , 49 ], predicting the progression of preneoplastic lesions [ 50 , 51 ], predicting response to treatment and prognosis [ 35 , 52 , 53 , 54 ], and even detecting malignant tumors years before conventional diagnosis [ 55 ]. Although different DNA methylation signatures are usually assessed for different tissues and outcomes, a common feature of cancers is global hypomethylation [ 17 , 56 , 57 ], in general associated with poor OS [ 58 , 59 , 60 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

HPV Infection Leaves a DNA Methylation Signature in Oropharyngeal Cancer Affecting Both Coding Genes and Transposable Elements

Camuzi¹,

Buexm²,

Lourenço

et al. 2021

HPV oncoproteins can modulate DNMT1 expression and activity, and previous studies have reported both gene-specific and global DNA methylation alterations according to HPV status in head and neck cancer. However, validation of these findings and a more detailed analysis of the transposable elements (TEs) are still missing. Here we performed pyrosequencing to evaluate a 5-CpG methylation signature and Line1 methylation in an oropharyngeal squamous cell carcinoma (OPSCC) cohort. We further evaluated the methylation levels of the TEs, their correlation with gene expression and their impact on overall survival (OS) using the TCGA cohort. In our dataset, the 5-CpG signature distinguished HPV-positive and HPV-negative OPSCC with 66.67% sensitivity and 84.33% specificity. Line1 methylation levels were higher in HPV-positive cases. In the TCGA cohort, Line1, Alu and long terminal repeats (LTRs) showed hypermethylation in a frequency of 60.5%, 58.9% and 92.3%, respectively. ZNF541 and CCNL1 higher expression was observed in HPV-positive OPSCC, correlated with lower methylation levels of promoter-associated Alu and LTR, respectively, and independently associated with better OS. Based on our findings, we may conclude that a 5-CpG methylation signature can discriminate OPSCC according to HPV status with high accuracy and TEs are differentially methylated and may regulate gene expression in HPV-positive OPSCC.

“…However, for comprehensive understanding of the carcinogenesis, characterization of epigenetic changes is also crucial. Unfortunately, for VSCC these changes have been interrogated in only a few studies [ 34 , 35 , 36 , 37 , 38 , 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…We observed that ZIC1 was hyper-methylated in both subtypes of VSCC, indicating an involvement of this gene in the HPV-independent pathway of VSCC carcinogenesis as well. A recent study reported an association between increasing methylation levels of ZIC1 and the risk of progression of VIN to VSCC [ 40 ]. One of the hyper-methylated DMGs in our study, DNMT3A , has been previously detected in VSCC, and was reported to correlate with a risk of recurrence [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Exploring Differentially Methylated Genes in Vulvar Squamous Cell Carcinoma

Dasgupta

Ewing‐Graham

Swagemakers

et al. 2021

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.