Dataset Information

Transcriptome Analysis in Vulvar Squamous Cell Cancer.

ABSTRACT: To date, therapeutic strategies in vulvar squamous cell carcinoma (VSCC) are lacking molecular pathological information and targeted therapy hasn't been approved in the treatment of VSCC, yet. Two etiological pathways are widely accepted: HPV induced vs. HPV independent, associated with chronic skin disease, often harboring TP53 mutations (mut). The aim of this analysis was to analyze the RNA expression patterns for subtype stratification on VSCC samples that can be integrated into the previously performed whole exome sequencing data for the detection of prognostic markers and potential therapeutic targets. We performed multiplex gene expression analysis (NanoString) with 770 genes in 24 prior next generation sequenced samples. An integrative data analysis was performed. Here, 98 genes were differentially expressed in TP53mut vs. HPV+ VSCC, in the TP53mut cohort, where 56 genes were upregulated and 42 were downregulated in comparison to the HPV+ tumors. Aberrant expression was primarily observed in cell cycle regulation, especially in HPV+ disease. Within the TP53mut group, a distinct cluster was identified that was correlated to a significantly worse overall survival (p = 0.017). The RNA expression profiles showed distinct patterns with regard to the known VSCC subtypes and could potentially enable further subclassification in the TP53mut groups.

SUBMITTER: Prieske K

PROVIDER: S-EPMC8699756 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Transcriptome Analysis in Vulvar Squamous Cell Cancer.

Prieske Katharina K Alawi Malik M Jaeger Anna A Wankner Maximilian Christian MC Eylmann Kathrin K Reuter Susanne S Lebok Patrick P Burandt Eike E Blessin Niclas C NC Schmalfeldt Barbara B Oliveira-Ferrer Leticia L Joosse Simon A SA Woelber Linn L

Cancers 20211219 24

To date, therapeutic strategies in vulvar squamous cell carcinoma (VSCC) are lacking molecular pathological information and targeted therapy hasn't been approved in the treatment of VSCC, yet. Two etiological pathways are widely accepted: HPV induced vs. HPV independent, associated with chronic skin disease, often harboring <i>TP53</i> mutations (mut). The aim of this analysis was to analyze the RNA expression patterns for subtype stratification on VSCC samples that can be integrated into the pr ...[more]

PMID: 34944992

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Project description:The study's aim was to investigate the immunohistochemical (IHC) expression of biological markers as potential prognostic/therapeutic factors in vulvar squamous cell carcinoma (VSCC). A series of 101 patients surgically treated at our center from 2016 to 2020 were retrospectively enrolled: 53 node-negative (Group A) and 48 node-positive (Group B). A total of 146 samples, 101 from primary tumor (T) and 45 from nodal metastases (N), were investigated. The IHC panel included: p16, p53, MLH1, MSH2, MSH6, PMS2, PD-L1, CD3, HER2/neu, ER, PR, EGFR, VEGF, and CD31. The reactions were evaluated on qualitative and semi-quantitative scales. Generalized Linear Model (GLM) and cluster analysis were performed in R statistical environment. A distance plot compared the IHC panel of T with the correspondent N. In Group A: p16-positive expression (surrogate of HPV-dependent pathway) was significantly higher (20.8% vs. 6.2%, p = 0.04). In Group B: PD-L1 positivity and high EGFR expression were found, respectively, in 77.1% and 97.9% patients (T and/or N). Overall, p16-negative tumors showed a higher PD-L1 expression (60.9% vs. 50.0%). In both groups: tumoral immune infiltration (CD3 expression) was mainly moderate/intense (80% vs. 95%); VEGF showed strong/moderate-diffuse expression in 13.9% of T samples; CD31, related to tumoral microvessel density (MVD), showed no difference between groups; a mutated p53 and over-expressed PD-L1 showed significant association with nodal metastasis, with Odds Ratios (OR) of 4.26 (CI 95% = 1.14-15.87, p = 0.03) and 2.68 (CI 95% = 1.0-7.19, p < 0.05), respectively; since all mismatch repair proteins (MMR) showed a retained expression and ER, PR, and HER2/neu were negative, they were excluded from further analysis. The cluster analysis identified three and four sub-groups of molecular profiles, respectively, in Group A and B, with no difference in prognosis. The molecular signature of each N and corresponding T diverged significantly in 18/41 (43.9%) cases. Our results support a potential role of immune checkpoint inhibitors and anti-VEGF and anti-EGFR drugs especially in patients with worse prognosis (metastatic, HPV-independent). A panel including EGFR, VEGF, PDL1, p16, and p53 might be performed routinely in primary tumor and repeated in case of lymph node metastases to identify changes in marker expression.

Project description:BackgroundVulvar squamous cell carcinoma (VSCC) is a relatively rare gynecologic cancer. Unlike cervical squamous cell carcinoma (CSCC), in which nearly all cases are caused by HPV infection, most VSCCs are HPV-independent. Patients with VSCC also have worse overall survival (OS) than those with CSCC. Unlike CSCC, the risk factors of VSCC have not been extensively studied. Here, we investigated the prognostic values of clinicopathological parameters as well as biomarkers in patients with VSCC.MethodsIn total, 69 cases of VSCC accessions were selected for analysis between April 2010 and October 2020. The risk factors of VSCC were screened using Cox models to establish nomograms for predicting survival outcomes.ResultsFollowing the multivariate COX model for OS, independent predictors including advanced age (hazard ratio [HR] 5.899, p = 0.009), HPV positivity (HR 0.092, p = 0.016), high Ki-67 index (HR 7.899, p = 0.006), PD-L1-positivity (HR 4.736, p = 0.077), and CD8 + tumor-infiltrating lymphocytes (TILs) (HR 0.214, p = 0.024) were included in the nomogram for OS; multivariate COX model for progression-free survival (PFS) was used to screen prognostic factors including advanced age (HR 2.902, p = 0.058), lymph node metastasis (HR 5.038, p = 0.056), HPV positivity (HR 0.116, p = 0.011), high Ki-67 index (HR 3.680, p = 0.042), PD-L1-positivity (HR 5.311, p = 0.045), and CD8 + TILs (HR 0.236, p = 0.014) to establish the PFS nomogram model. Based on the C-index (0.754 for OS and 0.754 for PFS) from our VSCC cohort and the corrected C-index (0.699 for OS and 0.683 for PFS) from an internal validation cohort, the nomograms demonstrated good predictive and discriminative ability. Kaplan-Meier curves also supported the excellent performance of the nomograms.ConclusionOur prognostic nomograms suggested that (1) shorter OS and PFS were associated with PD-L1-positivity, high Ki-67 index, and low CD8 + TILs; (2) HPV-independent tumors were associated with poorer survival outcome, and mutant p53 status showed no prognostic significance.

Dataset Information

Transcriptome Analysis in Vulvar Squamous Cell Cancer.

Publications

Transcriptome Analysis in Vulvar Squamous Cell Cancer.

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