Dataset Information

Inflammatory Proteins HMGA2 and PRTN3 as Drivers of Vulvar Squamous Cell Carcinoma Progression.

ABSTRACT: Current knowledge on the biology of squamous cell vulvar carcinoma (VSCC) is limited. We aimed to identify protein markers of VSCC tumors that would permit to stratify patients by progression risk. Early-stage tumors from patients who progressed (progVSCC) and from those who were disease-free (d-fVSCC) during follow-up, along with normal vulvar tissues were examined by mass spectrometry-based proteomics. Differentially expressed proteins (DEPs) were then verified in solid tissues and blood samples of patients with VSCC tumors and vulvar premalignant lesions. In progVSCC vs. d-fVSCC tumors, the immune response was the most over-represented Gene Ontology category for the identified DEPs. Pathway profiling suggested bacterial infections to be linked to aggressive VSCC phenotypes. High Mobility Group AT-Hook 2 (HMGA2) and Proteinase 3 (PRTN3) were revealed as proteins predicting VSCC progression. HMGA2 and PRTN3 abundances are associated with an aggressive phenotype, and hold promise as markers for VSCC patient stratification. It appears that vulvovaginal microflora disturbances trigger an inflammatory response contributing to cancer progression, suggesting that bacterial rather than viral infection status should be considered in the development of targeted therapies in VSCC.

SUBMITTER: Fatalska A

PROVIDER: S-EPMC7793473 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Inflammatory Proteins HMGA2 and PRTN3 as Drivers of Vulvar Squamous Cell Carcinoma Progression.

Fatalska Agnieszka A Rusetska Natalia N Bakuła-Zalewska Elwira E Kowalik Artur A Zięba Sebastian S Wroblewska Agnieszka A Zalewski Kamil K Goryca Krzysztof K Domański Dominik D Kowalewska Magdalena M

Cancers 20201223 1

Current knowledge on the biology of squamous cell vulvar carcinoma (VSCC) is limited. We aimed to identify protein markers of VSCC tumors that would permit to stratify patients by progression risk. Early-stage tumors from patients who progressed (progVSCC) and from those who were disease-free (d-fVSCC) during follow-up, along with normal vulvar tissues were examined by mass spectrometry-based proteomics. Differentially expressed proteins (DEPs) were then verified in solid tissues and blood sampl ...[more]

PMID: 33374674

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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:Oral squamous cell carcinoma (OSCC) is a major concern with high morbidity and mortality worldwide, even with the current knowledge and the advancement in treatment. OSCCs diagnosed at late-stage often require wide-excision with or without neck dissection, radiotherapy, or chemotherapy. When deemed successful, treatment often results in diminished quality of life, impaired function, and disfigurement. Strategies for early detection are urgently needed for patients afflicted with this disease. Inflammatory protein plasma biomarkers have shown to be potential tests for early detection and disease monitoring in several cancers. There has been no study on inflammation-related plasma biomarkers in OSCC. The objectives of the study were to use a multiplex approach to screen plasma-derived biomarkers and to examine the association of measurable proteins with OSCC. A total of 260 plasma samples (210 OSCC and 50 normal controls) were collected to measure for concentration of inflammatory related biomarkers using electrochemiluminescence multiplex assay. After screening of 82 potential biomarkers of the first 160 OSCC, 16 cytokines, chemokines, and growth factors were identified and verified in the second set of samples containing 50 OSCC and 50 normal. After adjustment of age and batch effects, the adjusted differential expression analysis showed that the OSCCs were markedly lower in 14 biomarkers and significantly higher level of interleukin 1 receptor antagonist (IL1Ra). By performing unsupervised clustering analysis, we observed distinctive groups of normal and two subgroups of OSCC. Linear regression of IL2, IL1Ra, and macrophage inhibitory factor (MIF) showed high accuracy in classifying OSCC with sensitivity of 0.96 and specificity of 0.92. In conclusion, this is the first paper to identify potential inflammatory plasma protein biomarkers of patients with OSCC. With further validation, the set of biomarkers can potentially be used to assist in early detection of OSCC when the disease is localized and in more treatable stage.

Project description:Importance:Molecular alterations in lichen sclerosus-associated vulvar squamous cell carcinoma (LS-VSCC) are largely unknown. Objective:To determine whether the retinoic acid receptor ? (RAR?) tumor-suppressor gene is involved in the onset and/or progression of LS-VSCC. Design, Setting, and Participants:The case-control study, conducted at University-Hospital of Ferrara, Italy, included 20 LS-VSCC (mean [SD] age, 75 [3] years) and 20 cancer-associated vulvar LS (caVLS; mean [SD] age, 62 [11] years) formalin-fixed embedded tissue specimens, 20 cancer-free vulvar LS (cfVLS), and 20 normal skin fresh specimens from diagnostic biopsies and women surgically treated for nonmalignant skin lesions, respectively. RAR? gene expression and promoter methylation were investigated in LS-VSCC and caVLS adjacent to VSCC specimens, and in cfVLS and normal skin specimens, as controls, by RT-Q real-time polymerase chain reaction (PCR) analysis, and sequencing of PCR-amplified bisulfite-treated DNA. c-Jun expression, an RAR? pathway-related gene, was also investigated. Main Outcomes and Measures:RAR? expression, correlation with its promoter methylation and c-Jun expression, and association with onset or progression of LS-VSCC. Results:In LS-VSCC, RAR? messenger RNA was 3.4-, 3.6-, and 4.8-fold lower than in caVLS (P?=?.001), cfVLS (P?=?.005), and normal skin (P?<?.001), respectively. The RAR? mRNA levels were similar in caVLS, cfVLS, and normal skin. The RAR? promoter was hypermethylated in 18 (90%) of 20 LS-VSCC, 11 (55%) of 20 cfVLS, 10 (50%) of 20 caVLS, and 5 (25%) of 20 in the normal skin group. The degree of methylation of RAR? promoter was higher in LS-VSCC, ranging from 5 to 9 (full promoter methylation) CpGs methylated, than in caVLS (P?=?.02), cfVLS (P?=?.03), or normal skin (P?<?.001), which was up to 5 CpGs methylated. Importantly, 0 of 8 LS-VSCC with 5 to 6 CpGs methylated and 5 (63%) of 8 LS-VSCC with 7 to 8 CpGs methylated were from patients with lymph node metastasis at diagnosis, respectively, whereas there were 2 of 2 (100%) LS-VSCC samples with 9 CpG methylated from patients with lymph node metastasis at diagnosis and subsequent recurrence. In LS-VSCC c-Jun mRNA was 4.3-, 1.4-, and 2.6-fold higher than in caVLS (P?<?.001), cfVLS (P?=?.001), and normal skin (P?<?.001), respectively. The expression of c-Jun was similar in caVLS, cfVLS, and normal skin. Conclusions and Relevance:Hypermethylation-induced RAR? down-expression was associated with LS-VSCC and correlates with the upregulation of c-Jun. The degree of methylation of RAR? promoter increased with the malignancy of LS-VSCC. Therefore, RAR? gene dysregulation may play a role in progression of LS-VSCC, and RAR? promoter methylation status may be used as a prognostic marker in clinical treatment of patients with LS-VSCC.

Dataset Information

Inflammatory Proteins HMGA2 and PRTN3 as Drivers of Vulvar Squamous Cell Carcinoma Progression.

Publications

Inflammatory Proteins HMGA2 and PRTN3 as Drivers of Vulvar Squamous Cell Carcinoma Progression.

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