Vulvar Squamous Cell Carcinoma: Comprehensive Genomic Profiling of HPV+ Versus HPV– Forms Reveals Distinct Sets of Potentially Actionable Molecular Targets

Williams, Erik; Werth, Adrienne; Sharaf, Radwa; Montesion, Meagan; Sokol, Ethan S.; Pavlick, Dean C.; McLaughlin-Drubin, Molly; Erlich, Rachel; Toma, Helen; Williams, Kevin Jon; Venstrom, J.; Alexander, Brian M.; Shah, Nikunj; Danziger, Natalie; Hemmerich, Amanda; Severson, Eric Allan; Killian, Jonathan Keith; Lin, Douglas I.; Ross, Jeffrey S.; Tse, Julie Y; Ramkissoon, Shakti; Mochel, Mark C.; Elvin, Julia A.

doi:10.1200/po.19.00406

Cited by 24 publications

(51 citation statements)

References 53 publications

(57 reference statements)

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“…In this study, we also investigated the molecular profile of a subset of dVIN and de-VIL, with a view to facilitate the identification of other potential diagnostic markers. In dVIN, TP53 and CDKN2A mutations were detected most frequently, in line with previous reports [ 47 , 54 , 55 , 56 , 57 , 58 , 59 ]. Interestingly, TP53 mutations were also detected in de-VIL, and dVIN that showed wild-type-expression on p53-IHC.…”

Section: Discussionsupporting

confidence: 91%

Evaluation of Immunohistochemical Markers, CK17 and SOX2, as Adjuncts to p53 for the Diagnosis of Differentiated Vulvar Intraepithelial Neoplasia (dVIN)

et al. 2021

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Histological diagnosis of differentiated vulvar intraepithelial neoplasia (dVIN), the precursor of human papillomavirus (HPV)-independent vulvar squamous cell carcinoma (VSCC), can be challenging, as features of dVIN may mimic those of non-dysplastic dermatoses. To aid the diagnosis, p53-immunohistochemistry (IHC) is commonly used, and mutant expression patterns are used to support a histological diagnosis of dVIN. However, a proportion of dVIN can show wild-type p53-expression, which is characteristic of non-dysplastic dermatoses. Furthermore, recent research has identified a novel precursor of HPV-independent VSCC—the p53-wild-type differentiated exophytic vulvar intraepithelial lesion (de-VIL). Currently, there are no established diagnostic IHC-markers for p53-wild-type dVIN or de-VIL. We evaluated IHC-markers, cytokeratin 17 (CK17), and SRY-box 2 (SOX2), as diagnostic adjuncts for dVIN. For this, IHC-expression of CK17, SOX2, and p53 was studied in dVIN (n = 56), de-VIL (n = 8), and non-dysplastic vulvar tissues (n = 46). For CK17 and SOX2, the percentage of cells showing expression, and the intensity and distribution of expression were recorded. We also performed next generation targeted sequencing (NGTS) on a subset of dVIN (n = 8) and de-VIL (n = 8). With p53-IHC, 74% of dVIN showed mutant patterns and 26% showed wild-type expression. Median percentage of cells expressing CK17 or SOX2 was significantly higher in dVIN (p53-mutant or p53-wild-type) and de-VIL than in non-dysplastic tissues (p < 0.01). Diffuse, moderate-to-strong, full epithelial expression of CK17 or SOX2 was highly specific for dVIN and de-VIL. With NGTS, TP53 mutations were detected in both dVIN and de-VIL. We infer that immunohistochemical markers CK17 and SOX2, when used along with p53, may help support the histological diagnosis of dVIN.

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Section: Discussionsupporting

confidence: 91%

Evaluation of Immunohistochemical Markers, CK17 and SOX2, as Adjuncts to p53 for the Diagnosis of Differentiated Vulvar Intraepithelial Neoplasia (dVIN)

et al. 2021

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“…Genomic changes in the form of somatic mutations can alter gene expression and drive the carcinogenesis. For VSCC and its precursor lesion, vulvar intraepithelial neoplasia (VIN), somatic mutations have been investigated in several studies using targeted (amplicon panel-based) sequencing, or whole exome sequencing [ 7 , 10 , 11 , 12 , 18 , 29 , 30 , 31 , 32 , 33 ]. However, for comprehensive understanding of the carcinogenesis, characterization of epigenetic changes is also crucial.…”

Section: Discussionmentioning

confidence: 99%

“…For the identification of biomarkers of potential diagnostic, prognostic, predictive, or therapeutic interest, comprehensive molecular characterization of cancer, by comparing molecular profiles of cancer and normal tissue from the same anatomical site is essential [ 17 ]. In recent years, several studies have investigated genomic changes, e.g., somatic mutations and copy number variations in VSCC, and its precursor lesion, vulvar intraepithelial neoplasia (VIN) [ 7 , 10 , 11 , 12 , 18 ]. However, the epigenomic changes in VSCC remain relatively underexplored.…”

Section: Introductionmentioning

confidence: 99%

Exploring Differentially Methylated Genes in Vulvar Squamous Cell Carcinoma

Dasgupta

Ewing‐Graham

Swagemakers

et al. 2021

Cancers

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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.

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“…One study evaluated the molecular profiles in primary and metastatic VSCC in a subset of cases [29]. Eight studies (57%) analyzed only somatic mutations [25,28,[30][31][32][33][34][35], two studies (14%) focused only on copy number alterations [36,37], and four (28%) included both somatic mutation profiling and analysis of copy number alterations [27,29,38,39]. Twelve studies (86%) applied NGS.…”

Section: Resultsmentioning

confidence: 99%

Molecular Landscape of Vulvar Squamous Cell Carcinoma

Carreras-Dieguez

Guerrero

Rodrigo-Calvo

et al. 2021

IJMS

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Vulvar squamous cell carcinoma (VSCC) is a rare malignancy with dual pathogenesis, Human papillomavirus (HPV)-associated and HPV-independent, with a poorly explored molecular landscape. We aimed to summarize the findings of the series analyzing molecular hallmarks of this neoplasm. In January 2021, we conducted a comprehensive literature search using Pubmed Medline and Scopus to identify publications focused on genomic profiling of VSCC. Observational studies, including both prospective and retrospective designs, evaluating molecular alterations in VSCC were deemed eligible. A total of 14 studies analyzing 749 VSCC were identified. The study series were heterogeneous in HPV testing and sequencing strategies, included small sets of tumors and cancer genes, and commonly lacked survival analysis. Only one extensive targeted next-generation sequencing-based study comprised a large cohort of 280 VSCC. The mutated genes, their number, and frequencies were highly variable between the series. Overall, TP53 and CDKN2A, followed by PIK3CA, HRAS, and PTEN, were the most frequently studied and mutated genes. Mutations involved in the PI3K/AKT/mTOR pathway, including TP53, HRAS, KRAS, and PIK3CA, have been consistently reported across the studies. However, the role of individual mutations or pathways in the development of VSCC remains unclear. In conclusion, heterogeneity and the small sample size of available molecular series contribute to a limited view of the molecular landscape of VSCC. Large-scale genome- or exome-wide studies with robust HPV testing are necessary to improve the molecular characterization of VSCC.

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Vulvar Squamous Cell Carcinoma: Comprehensive Genomic Profiling of HPV+ Versus HPV– Forms Reveals Distinct Sets of Potentially Actionable Molecular Targets

Cited by 24 publications

References 53 publications

Evaluation of Immunohistochemical Markers, CK17 and SOX2, as Adjuncts to p53 for the Diagnosis of Differentiated Vulvar Intraepithelial Neoplasia (dVIN)

Evaluation of Immunohistochemical Markers, CK17 and SOX2, as Adjuncts to p53 for the Diagnosis of Differentiated Vulvar Intraepithelial Neoplasia (dVIN)

Exploring Differentially Methylated Genes in Vulvar Squamous Cell Carcinoma

Molecular Landscape of Vulvar Squamous Cell Carcinoma

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