Integrative bioinformatics approaches to map key biological markers and therapeutic drugs in Extramammary Paget's disease of the scrotum.
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ABSTRACT:
SUBMITTER: Noor F
PROVIDER: S-EPMC8297842 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and aims: Ovarian cancer (OC) is the seventh most commonly detected cancer among women. This study aimed to map the hub and core genes and potential pathways that might be involved in the molecular pathogenesis of OC. Methods: In the present work, we analyzed a microarray dataset (GSE126519) from the Gene Expression Omnibus (GEO) database and used the GEO2R tool to screen OC cells and ovarian SINE-resistant cancer cells for differentially expressed genes (DEGs). For the functional annotation of the DEGs, we conducted Gene Ontology (GO) and pathway enrichment analyses (KEGG) using the DAVID v6.8 online server and GenoGo Metacore™, Cortellis Solution software. Protein-protein interaction (PPI) networks were constructed using the STRING database, and Cytoscape software was used for visualization. The survival analysis was performed using the online platform GEPIA2 to determine the prognostic value of the expression of hub genes in cell lines from OC patients. Results: We identified a total of 809 upregulated and 700 downregulated DEGs. GO analysis revealed that the genes with statistically significant differences in expression were mainly associated with biological processes involved in the cell cycle, the mitotic cell cycle, mitotic nuclear division, organ morphogenesis, cell development, and cell morphogenesis. By using the Analyze Networks (AN) algorithm in GeneGo, we identified the most relevant biological networks involving DEGs that were mainly enriched in the cell cycle (in metaphase checkpoints) and revealed the role of APC in cell cycle regulation pathways. We found 10 hub genes and four core genes (FZD6, FZD8, CDK2, and RBBP8) that are strongly linked to OC. Conclusion: This study sheds light on the molecular pathogenesis of OC and is expected to provide potential molecular biomarkers that are beneficial for the treatment and clinical molecular diagnosis of OC.
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Project description:Extramammary Paget's disease (EMPD) is a rare, slow-growing, cutaneous adenocarcinoma that usually originates in the anogenital area and axillae outside the mammary glands. EMPD mostly progresses slowly and is often diagnosed as carcinoma in situ; however, upon becoming invasive, it promptly and frequently metastasizes to regional lymph nodes, leading to subsequent distant metastasis. To date, several chemotherapy regimens have been used to treat metastatic EMPD; however, they present limited effect and patients with distant metastasis exhibit a poor prognosis. Recently, basic and translational investigative research has elucidated factors and molecular mechanisms underlying the promotion of metastasis, which can lead to targeted therapy-based emerging treatment strategies. Here, we aim to discuss current therapies and their limitations; advancements in illustrating mechanisms promoting invasion, migration, and proliferation of EMPD tumor cells; and future therapeutic approaches for metastatic EMPD that may enhance clinical outcomes.
| S-EPMC5820294 | biostudies-literature
Project description:Extramammary Paget's disease (EMPD) is a rare skin cancer arising in the apocrine gland-rich areas. Most EMPD tumors are dormant, but metastatic lesions are associated with poor outcomes owing to the lack of effective systemic therapies. Trophoblast cell surface antigen 2 (Trop2), a surface glycoprotein, has drawn attention as a potential therapeutic target for solid tumors. Sacituzumab govitecan, an antibody-drug conjugate of Trop2, has recently entered clinical use for the treatment of various solid cancers. However, little is known about the role of Trop2 in EMPD. In this study, we immunohistochemically examined Trop2 expression in 116 EMPD tissue samples and 10 normal skin tissues. In normal skin, Trop2 was expressed in the epidermal keratinocytes, inner root sheaths, and infundibulum/isthmus epithelium of hair follicles, eccrine/apocrine glands, and sebaceous glands. Most EMPD tissues exhibited homogeneous and strong Trop2 expression, and high Trop2 expression was significantly associated with worse disease-free survival (p = 0.0343). These results suggest the potential use of Trop2-targeted therapy for EMPD and improve our understanding of the skin-related adverse effects of current Trop2-targeted therapies such as sacituzumab govitecan.
| S-EPMC8304908 | biostudies-literature
Project description:Extramammary Paget's disease (EMPD) is a rare and lethal intraepithelial malignancy that remains poorly understood. No standardized guidelines or consensus statements exist with regards to the diagnostic evaluation, therapeutic approaches and follow-up management. Complete surgical excision with negative margins has been accepted as the mainstay of treatment for EMPD to decrease the risk of local recurrence and to maximize durable cure. Non-invasive therapies, such as laser therapy, photodynamic therapy, radiotherapy and topical chemotherapy have been utilized, but are best reserved for non-surgical candidates. While the debate on the surgical approach between wide local excision (WLE) and Mohs micrographic surgery (MMS) continues, several studies have demonstrated the ability of WLE to be performed safely and effectively and to yield equally satisfactory outcomes with similar rates of recurrence to MMS. Patients undergoing surgical excision often require complex closures with skin grafting or local flaps to close genital defects. We aim to provide an up-to-date review of the current knowledge of EMPD. In addition to discussing the clinical presentation and prognostic outcomes, we focus and elaborate on the diagnostic approaches and treatment alternatives available. This information may serve as a primer for the urologist who may be called upon to treat this malignancy primarily or to provide wound coverage secondarily.
| S-EPMC6995936 | biostudies-literature
Project description:The efficacy and survival impact of conventional chemotherapies for metastatic extramammary Paget's disease (EMPD) have not been fully elucidated. This study examined the long-term outcome of chemotherapy for this indication. We conducted a retrospective review of 21 patients with distant metastatic EMPD (14 patients treated with chemotherapy and 7 patients treated without chemotherapy). The response rate of chemotherapy and patient survival were statistically analyzed. Among the 14 patients treated with chemotherapy, 12, 1, and 1 patient received docetaxel, paclitaxel, and low-dose 5-fluorouracil plus cisplatin, respectively, as the first-line treatment. The response rate was 50.0% (7/14), and the disease control rate was 64.3% (9/14). The median progression-free survival (PFS) and overall survival (OS) were 16.8 and 27.9 months, respectively. Multivariate analyses revealed that chemotherapy was a significant factor for prolonged PFS (hazard ratio (HR) 0.22, p = 0.038) but not for OS (HR = 1.71, p = 0.54). Ten patients (71.4%) had severe (grade 3 or 4) hematological adverse events. Although conventional chemotherapy improved PFS, we failed to show a significantly improved OS. Considering the frequent adverse events of conventional chemotherapy, targeted therapy may become a mainstay for the treatment of metastatic EMPD.
| S-EPMC7918098 | biostudies-literature
Project description:BackgroundExtramammary Paget's disease (EMPD) is a rare cutaneous malignancy, commonly affecting the external genitalia and perianal area of the elderly with unclear pathogenesis. Metabolomics provides a novel perspective for uncovering the metabolic mechanisms of a verity of cancers.Materials and methodsHere, we explored the metabolome of EMPD using an untargeted strategy. In order to further investigate the potential relationship between metabolites and gene expression, we re-analyzed the gene expression microarray data (GSE117285) using differential expression analysis and functional enrichment analyses.ResultsResults showed that a total of 896 metabolites were identified and 87 metabolites including 37 upregulated and 50 downregulated significantly in EMPD were sought out. In the following feature selection analyses, four metabolites, namely, cyclopentyl fentanyl-d5, LPI 17:0, guanosine-3',5'-cyclic monophosphate, kynurenine (KYN, high in EMPD) were identified by both random forest and support vector machine analyses. We then identified 1,079 dysfunctional genes: 646 upregulated and 433 downregulated in EMPD. Specifically, the tryptophan-degrading enzyme including indoleamine-2,3-dioxygenase-1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) were also increased. Generally, cancers exhibit a high expression of IDO1 and TDO2 to catabolize tryptophan, generating abundant KYN. Moreover, we also noticed the abnormal activation of sustaining proliferative signaling in EMPD.ConclusionIn conclusion, this study was the first to reveal the metabolome profile of EMPD. Our results demonstrate that IDO1/TDO2-initialized KYN metabolic pathway may play a vital role in the development and progression of EMPD, which may serve as a potential therapeutic target for treating EMPD.
| S-EPMC10859479 | biostudies-literature
Project description:BackgroundThe outcome of extramammary Paget's disease (EMPD) is poor when it progresses to metastasis because of the lack of effective systemic therapies. Recently, CDK4-targeted therapy has attracted attention as a potential therapeutic target for some cancers. The aim of this study was to analyze the impact of CDK4 expression on the survival of patients with EMPD.MethodsWe retrospectively reviewed 110 patients with EMPD. We conducted immunohistochemical analysis of CDK4 and cyclin D1 expression, and assessed the association between their expression and survival.ResultsMost EMPD lesions (108/110, 98.2%) were positive for CDK4 staining and there was a positive correlation between CDK4 expression and cyclin D1 expression (r = 0.54, p < 0.001). Tumor thickness (p = 0.0003) and the presence of regional lymph node metastasis (p = 0.015) were significantly associated with high CDK4 expression. Regarding invasive EMPD, the multivariate analysis did not show the correlation between the expression of CDK4/cyclin D1 and survival outcomes (HR: 3.14, p = 0.14).ConclusionThe overexpression of CDK4 was identified as a major risk factor for disease progression. CDK4-targeted therapy could thus be a novel treatment option for unresectable EMPD.
| S-EPMC8358779 | biostudies-literature
Project description:Extramammary Paget's disease (EMPD) is a neoplastic skin disease of indeterminate origin with an unknown genetic cause. We performed a comprehensive genetic analysis or targeted gene sequencing in 48 patients with EMPD. We identified FOXA1 mutations, a GAS6-FOXA1 fusion gene, and somatic hotspot mutations in the FOXA1 promoter region in 11 of the 48 EMPD patients (11/48, 23%). Additional mutations were identified in PIK3CA (six patients) and in HIST1H2BB, HIST1H2BC, and SMARCB1 (one patient each), but none were found in other frequently mutated genes in cancer. A global gene expression analysis using EMPD clinical samples found the upregulation of PI3 kinase-AKT-mTOR signaling. ABCC11, which is specifically expressed in the apocrine secretory cells and is necessary for their sweat secretion, was upregulated in the EMPD samples. This upregulation suggests that Paget cells originate from apocrine secretory cells. Immunohistochemical staining revealed that FOXA1 expression was prevalent in all of the EMPD samples analyzed and was associated with estrogen receptor expression. Our genetic analysis indicates that EMPD frequently involves FOXA1 mutations. FOXA1 is a transcriptional pioneer factor for the estrogen receptor, and the present results suggest that certain treatments for hormone-dependent cancers could be effective for EMPD.
| S-EPMC7226542 | biostudies-literature
Project description:Cancer immunotherapy has highlighted the clinical relevance of enhancing anti-tumor response of CD8+ T cells in several cancer types. Little is known, however, about the involvement of the immune system in extramammary Paget's disease (EMPD). We examined the cytotoxicity and the effector functions of CD8+ T cells using paired samples of peripheral blood and tumors by flow cytometry. Expression levels of perforin, granzyme B, IFN-g, TNF-a, and IL-2 in CD8+ tumor-infiltrating lymphocytes (TILs) were significantly lower than those in CD8+ T cells of peripheral blood. Significantly higher expression of PD-1 was found in CD8+TILs than in CD8+ T cells of peripheral blood. A high number of CD8+ cells was significantly associated with poor overall survival (OS) adjusted with age, sex, and clinical stage (hazard ratio [HR] = 5.03, P = 0.045, 95% confidence interval [CI] 1.03-24.4). On the other hand, the number of PD-1+ cells was not associated with OS or disease-free survival (DFS). Moreover, we found that tumor cells produced immunosuppressive molecule indoleamine 2,3-dyoxygenae (IDO). In conclusion, CD8+ TILs displayed an exhausted phenotype in EMPD. IDO expression seemed more relevant in inducing CD8 exhaustion than PD-1 upregulation or PD-L1 expression by immune cells. Restoring the effector functions of CD8+ TILs could be an effective treatment strategy for advanced EMPD.
| S-EPMC6347258 | biostudies-literature
Project description:BACKGROUND:Extramammary Paget's disease (EMPD), a rare skin malignancy with non-specific manifestations, is often misdiagnosed as eczema of scrotum or tinea cruris. Although the diagnosis of EMPD could be confirmed by biopsy, it can be delayed as patients are reluctant to receive invasive operations. Herein, we investigated the serum miRNA expressions of EMPD patients and compared to that of the eczema of scrotum or tinea cruris patients as well as health volunteers for potential diagnostic markers for EMPD. METHODS:Altogether 45 subjects including 16 patients diagnosed with EMPD, 12 patients diagnosed with eczema of scrotum or tinea cruris and 17 healthy volunteers were enrolled in this study. Serum from all of subjects were collected to identify miRNAs (by miRNA array global normalization, RT-PCR validation, and receiver operating characteristic curve analysis) that could be potential diagnostic markers for EMPD. RESULTS:The miRNA array analyses revealed that the expressions of 37 miRNAs from the EMPD patients were different (change ?4-fold) from health volunteers. Among these miRNAs, the expression of miR-155 was significantly increased (p?<?0.01) in the EMPD patients as compared with that of the health volunteers and the eczema of scrotum or the tinea cruris patients (no difference between these two control groups). In addition, receiver operating characteristic (ROC) curve analysis showed that diagnostic capacities (defined as the area under curve of ROC) of miR-155 are 0.85 (as compared with health volunteers group) and 0.81 (as compared with the eczema of scrotum or the tinea cruris patients group), respectively. CONCLUSION:The serum miRNA expression of gene miR-155 in the EMPD patients was differentiated from that of other subjects warranting further validation of miR-155 as a diagnostic marker of EMPD.
| S-EPMC6247506 | biostudies-other