RESUMEN
Epithelial ovarian cancer (EOC) is widely recognized as the most lethal gynecological malignancy; however, its early-stage detection remains a considerable clinical challenge. To address this, we have introduced a new method, named Comprehensive Serum Glycopeptide Spectral Analysis (CSGSA), which detects early-stage cancer by combining glycan alterations in serum glycoproteins with tumor markers. We detected 1712 glycopeptides using liquid chromatography-mass spectrometry from the sera obtained from 564 patients with EOC and 1149 controls across 13 institutions. Furthermore, we used a convolutional neural network to analyze the expression patterns of the glycopeptides and tumor markers. Using this approach, we successfully differentiated early-stage EOC (Stage I) from non-EOC, with an area under the curve (AUC) of 0.924 in receiver operating characteristic (ROC) analysis. This method markedly outperforms conventional tumor markers, including cancer antigen 125 (CA125, 0.842) and human epididymis protein 4 (HE4, 0.717). Notably, our method exhibited remarkable efficacy in differentiating early-stage ovarian clear cell carcinoma from endometrioma, achieving a ROC-AUC of 0.808, outperforming CA125 (0.538) and HE4 (0.557). Our study presents a promising breakthrough in the early detection of EOC through the innovative CSGSA method. The integration of glycan alterations with cancer-related tumor markers has demonstrated exceptional diagnostic potential.
Asunto(s)
Biomarcadores de Tumor , Carcinoma Epitelial de Ovario , Glicopéptidos , Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/sangre , Carcinoma Epitelial de Ovario/diagnóstico , Carcinoma Epitelial de Ovario/patología , Biomarcadores de Tumor/sangre , Neoplasias Ováricas/sangre , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/patología , Glicopéptidos/sangre , Persona de Mediana Edad , Curva ROC , Antígeno Ca-125/sangre , Estadificación de Neoplasias , Adulto , Anciano , Cromatografía Liquida/métodos , Detección Precoz del Cáncer/métodos , Estudios de Casos y Controles , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/análisis , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/metabolismoRESUMEN
BACKGROUND: High-grade Epithelial Ovarian Cancer (HGEOC) is an aggressive disease that usually presents at an advanced stage. Thus, detecting the circulating cytokines (IFNγ and TNF-α) may serve as a biomarker to identify malignancy and manage therapeutic decisions. OBJECTIVES: Assessing the clinical importance of inflammatory mediators and tumor markers in EOC Egyptian patients compared with benign cases. Moreover, identifying the distinct inflammatory mediators in EOC patients combined with HPV infection. METHODS: This study was conducted on 61 Egyptian patients, divided into 25 patients with HGEOC, 22 patients with LGEOC, and 14 benign ovarian tumor cases. Measurements of serum HE4, CA125, CEA, and CA19-9 were determined by Roche Elecsys immunoassays. Serum levels of TNF-α and IFN-γ were measured using quantitative sandwich ELISA. Quantitative genotyping of HPV DNA types 16, 18, and 45 was assessed for the HPV DNA-positive samples. RESULTS: HPV DNA was detected in 25.53 % of malignant cases, HPV 16 was detected in 50 % of HPV-positive cases, and only 1 case of HPV 18 was detected out of 12 positive cases. The Human Epididymis protein 4 (HE4) was statistically different between patients with EOC and benign cases (p-value = 0.007) and between HPV DNA positive and HPV DNA negative cases (p-value = 0.008). The serum levels of IFN- γ were statistically different between HGEOC and LGEOC (p-value < 0.001), while the serum levels of TNF-α didn't differ statistically between the two groups. CONCLUSION: IFN-γ could be used as a biomarker to discriminate HGEOC and LGEOC. Initial evidence for the possible association between HE4 and the progression of HPV-associated EOC was speculated.
Asunto(s)
Carcinoma Epitelial de Ovario , Interferón gamma , Neoplasias Ováricas , Infecciones por Papillomavirus , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP , Humanos , Femenino , Infecciones por Papillomavirus/sangre , Infecciones por Papillomavirus/inmunología , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/diagnóstico , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/análisis , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/metabolismo , Egipto , Interferón gamma/sangre , Persona de Mediana Edad , Carcinoma Epitelial de Ovario/sangre , Carcinoma Epitelial de Ovario/diagnóstico , Adulto , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/diagnóstico , Biomarcadores de Tumor/sangre , Anciano , Factor de Necrosis Tumoral alfa/sangre , Papillomaviridae , Relevancia ClínicaRESUMEN
Human epididymis protein 4 (HE4), a diagnostic biomarker of ovarian cancer, is crucial for monitoring the early stage of the disease. Hence, it is highly important to develop simple, inexpensive, and user-friendly biosensors for sensitive and quantitative HE4 assays. Herein, a new sandwich-type electrochemical immunosensor based on Prussian blue (PB) as a signal indicator and functionalized metal-organic framework nanocompositesas efficient signal amplifiers was fabricated for quantitative analysis of HE4. In principle, ketjen black (KB) and AuNPs modified on TiMOF (TiMOF-KB@AuNPs) could accelerate electron transfer on the electrode surface and act as a matrix for the immobilization of antibodies via cross-linking to improve the determination sensitivity. The PB that covalently binds to labeled antibodies endows the biosensors with intense electrochemical signals. Furthermore, the concentration of HE4 could be indirectly detected by monitoring the electroactivity of PB. Benefiting from the high signal amplification ability of the PB and MOF nanocomposites, this strategy displayed a wide linear range (0.1-80 ng mL-1) and a lower detection limit (0.02 ng mL-1). Hence, this study demonstrated great promise for application in clinical ovarian cancer diagnosis and treatment, and provided a new platform for detecting other cancer biomarkers.
Asunto(s)
Técnicas Biosensibles , Técnicas Electroquímicas , Ferrocianuros , Oro , Límite de Detección , Estructuras Metalorgánicas , Neoplasias Ováricas , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP , Técnicas Biosensibles/métodos , Humanos , Estructuras Metalorgánicas/química , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/análisis , Ferrocianuros/química , Técnicas Electroquímicas/métodos , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/sangre , Femenino , Oro/química , Nanopartículas del Metal/química , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/análisis , Inmunoensayo/métodos , Anticuerpos Inmovilizados/química , Nanocompuestos/químicaRESUMEN
OBJECTIVE: The prognosis of lung adenocarcinoma (LUAD), which is the most common type of lung cancer, remains poor. Little is known about the function and mechanism of whey acidic protein four-disulfide core domain 2 (WFDC2) in LUAD. METHODS: In this study, we used online databases to compare WFDC2 expression between LUAD and normal tissues, to analyze the relationship between WFDC2 and overall survival, and to investigate the potential roles of WFDC2. RESULTS: We found that WFDC2 protein and mRNA expression levels were significantly higher in LUAD tissue than in normal tissue, and high WFDC2 mRNA expression was associated with better overall survival. WFDC2 mRNA expression was correlated with the mutation status of TP53. The biological function of WFDC2 was associated with the cell cycle, and low WFDC2 mRNA expression was associated with an elevated tumor mutational burden and neoantigen levels. A negative relationship was observed between WFDC2 and immune gene expression, and high WFDC2 mRNA expression was found in patients with LUAD and low programed cell death 1 mRNA expression. CONCLUSIONS: We propose that WFDC2 is associated with clinical benefits of immune checkpoint inhibitors in LUAD.
Asunto(s)
Adenocarcinoma del Pulmón , Biomarcadores de Tumor , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares , Humanos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Pronóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/metabolismo , Inmunoterapia/métodos , Masculino , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/metabolismo , Femenino , Mutación , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Persona de Mediana Edad , Inhibidores de Puntos de Control Inmunológico/uso terapéuticoRESUMEN
Ovarian cancer is the 8th most common cancer among women and has a 5-year survival of only 30-50%. While the survival is close to 90% for stage I tumours it is only 20% for stage IV. Current biomarkers are not sensitive nor specific enough, and novel biomarkers are urgently needed. We used the Explore PEA technology for large-scale analysis of 2943 plasma proteins to search for new biomarkers using two independent clinical cohorts. The discovery analysis using the first cohort identified 296 proteins that had significantly different levels in malign tumours as compared to benign and for 269 (91%) of these, the association was replicated in the second cohort. Multivariate modelling, including all proteins independent of their association in the univariate analysis, identified a model for separating benign conditions from malign tumours (stage I-IV) consisting of three proteins; WFDC2, KRT19 and RBFOX3. This model achieved an AUC of 0.92 in the replication cohort and a sensitivity and specificity of 0.93 and 0.77 at a cut-off developed in the discovery cohort. There was no statistical difference of the performance in the replication cohort compared to the discovery cohort. WFDC2 and KRT19 have previously been associated with ovarian cancer but RBFOX3 has not previously been identified as a potential biomarker. Our results demonstrate the ability of using high-throughput precision proteomics for identification of novel plasma protein biomarker for ovarian cancer detection.
Asunto(s)
Biomarcadores de Tumor , Neoplasias Ováricas , Proteómica , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP , Humanos , Femenino , Neoplasias Ováricas/sangre , Neoplasias Ováricas/diagnóstico , Biomarcadores de Tumor/sangre , Proteómica/métodos , Persona de Mediana Edad , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/análisis , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/metabolismo , Queratina-19/sangre , Anciano , Adulto , Estudios de Cohortes , Estadificación de NeoplasiasRESUMEN
It has been shown that the high expression of human epididymis protein 4 (HE4) in most lung cancers is related to the poor prognosis of patients, but the mechanism of pathological transformation of HE4 in lung cancer is still unclear. The current study is expected to clarify the function and mechanism of HE4 in the occurrence and metastasis of lung adenocarcinoma (LUAD). Immunoblotting evaluated HE4 expression in lung cancer cell lines and biopsies, and through analysis of The Cancer Genome Atlas (TCGA) dataset. Frequent HE4 overexpression was demonstrated in LUAD, but not in lung squamous cell carcinoma (LUSC), indicating that HE4 can serve as a biomarker to distinguish between LUAD and LUSC. HE4 knockdown significantly inhibited cell growth, colony formation, wound healing, and invasion, and blocked the G1-phase of the cell cycle in LUAD cell lines through inactivation of the EGFR signaling downstream including PI3K/AKT/mTOR and RAF/MAPK pathways. The first-line EGFR inhibitor gefitinib and HE4 shRNA had no synergistic inhibitory effect on the growth of lung adenocarcinoma cells, while the third-line EGFR inhibitor osimertinib showed additive anti-proliferative effects. Moreover, we provided evidence that HE4 regulated EGFR expression by transcription regulation and protein interaction in LUAD. Our findings suggest that HE4 positively modulates the EGFR signaling pathway to promote growth and invasiveness in LUAD and highlight that targeting HE4 could be a novel strategy for LUAD treatment.
Asunto(s)
Adenocarcinoma del Pulmón , Receptores ErbB , Neoplasias Pulmonares , Invasividad Neoplásica , Transducción de Señal , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP , Animales , Humanos , Ratones , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Receptores ErbB/metabolismo , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas/metabolismo , Proteínas/genética , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/genética , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/metabolismoRESUMEN
Objective: To establish and validate a prediction model for early-stage epithelial ovarian cancer based on least absolute shrinkage and selection operator (LASSO) regression. Methods: A total of 509 cases ovarian mass patients who underwent surgical treatment in Tianjin Medical General Hospital from January 2018 to March 2023 were retrospectively analyzed. The patients were randomly divided into modeling group [n=356, M(Q1,Q3) for age were 43 (31, 61) years] and internal validation group [n=153, age 42 (31, 60) years] by 7â¶3 ratio. In addition, 86 patients [age 44 (33, 61) years] who underwent surgical treatment for ovarian mass in Tianjin Medical University General Hospital from April to November 2023 were collected as external validation group. The variables were screened by LASSO regression. The nomogram model was established and plotted by multivariate logistic regression. Internal and external validation were then conducted. The model performance and clinical applicability were evaluated using receiver operating characteristic (ROC) curve, calibration curve and decision curve. Results: Five variables including age (OR=1.040,95%CI:1.000-1.050,P=0.002), carbohydrate antigen 125 (CA125) (OR=1.001, 95%CI: 1.000-1.010, P=0.017), human epididymis protein 4 (HE4) (OR=1.020, 95%CI: 1.000-1.030, P=0.002), carbohydrate antigen 199 (CA199) (OR=1.001, 95%CI:1.000-1.020, P=0.023) and lactate dehydrogenase (LDH) (OR=1.020, 95%CI: 1.010-1.022, P=0.001) were screened as risk factors for early-stage epithelial ovarian cancer. The nomogram model was constructed based on these above five risk factors to predict early-stage epithelial ovarian cancer. ROC curves showed the area under curve (AUC) were 0.915(95%CI:0.910-0.932)for modeling group, 0.891(95%CI:0.874-0.905) for internal validation group, and 0.924(95%CI:0.907-0.942) for external verification. The calibration curves and clinical decision curves showed the model exhibited good consistency and clinical practicability. Conclusions: The nomogram model built includes age, CA125, HE4, CA199, and LDH. It can effectively predict early-stage epithelial ovarian cancer and has strong clinical practicability.
Asunto(s)
Carcinoma Epitelial de Ovario , Nomogramas , Neoplasias Ováricas , Humanos , Femenino , Persona de Mediana Edad , Carcinoma Epitelial de Ovario/patología , Neoplasias Ováricas/patología , Adulto , Estudios Retrospectivos , Antígeno Ca-125/sangre , Curva ROC , Estadificación de Neoplasias , Modelos Logísticos , Factores de Riesgo , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/análisisRESUMEN
Ovarian cancer (OC) has an unfavorable prognosis. Due to the lack of effective screening tests, new diagnostic methods are being sought to detect OC earlier. The aim of this study was to evaluate the concentration and diagnostic utility of selected matrix metalloproteinases (MMPs) as OC markers in comparison with HE4, CA125 and the ROMA algorithm. The study group consisted of 120 patients with OC; the comparison group consisted of 70 patients with benign lesions and 50 healthy women. MMPs were determined via the ELISA method, HE4 and CA125 by CMIA. Patients with OC had elevated levels of MMP-3 and MMP-11, similar to HE4, CA125 and ROMA values. The highest SE, SP, NPV and PPV values were found for MMP-26, CA125 and ROMA in OC patients. Performing combined analyses of ROMA with selected MMPs increased the values of diagnostic parameters. The topmost diagnostic power of the test was obtained for MMP-26, CA125, HE4 and ROMA and performing combined analyses of MMPs and ROMA enhanced the diagnostic power of the test. The obtained results indicate that the tested MMPs do not show potential as stand-alone OC biomarkers, but can be considered as additional tests to raise the diagnostic utility of the ROMA algorithm.
Asunto(s)
Algoritmos , Biomarcadores de Tumor , Antígeno Ca-125 , Metaloproteinasa 2 de la Matriz , Neoplasias Ováricas , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP , Humanos , Femenino , Neoplasias Ováricas/sangre , Neoplasias Ováricas/diagnóstico , Antígeno Ca-125/sangre , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/análisis , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/metabolismo , Persona de Mediana Edad , Biomarcadores de Tumor/sangre , Adulto , Anciano , Metaloproteinasa 2 de la Matriz/sangre , Proteínas/metabolismo , Proteínas/análisis , Metaloproteinasas de la Matriz/sangre , Metaloproteinasas de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/sangre , Proteínas de la Membrana/sangre , Proteínas de la Membrana/metabolismo , Estudios de Casos y Controles , Curva ROC , Metaloproteinasa 11 de la Matriz/sangre , Metaloproteinasa 11 de la Matriz/metabolismoRESUMEN
Comprehensive biomedical proteomic datasets are accumulating exponentially, warranting robust analytics to deconvolute them for identifying novel biological insights. Here, we report a strategic machine learning (ML)-based feature extraction workflow that was applied to unveil high-performing protein markers for high-grade serous ovarian carcinoma (HGSOC) from publicly available ovarian cancer tissue and serum proteomics datasets. Diagnosis of HGSOC, an aggressive form of ovarian cancer, currently relies on diagnostic methods based on tissue biopsy and/or non-specific biomarkers such as the cancer antigen 125 (CA125) and human epididymis protein 4 (HE4). Our newly developed ML-based approach enabled the identification of new serum proteomic biomarkers for HGSOC. The performance verification of these marker combinations using two independent cohorts affirmed their outperformance against known biomarkers for ovarian cancer including clinically used serum markers with >97% AUC. Our analysis also added novel biological insights such as enriched cancer-related processes associated with HGSOC.
Asunto(s)
Biomarcadores de Tumor , Aprendizaje Automático , Neoplasias Ováricas , Proteómica , Humanos , Femenino , Neoplasias Ováricas/sangre , Biomarcadores de Tumor/sangre , Proteómica/métodos , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/análisis , Cistadenocarcinoma Seroso/sangre , Antígeno Ca-125/sangreRESUMEN
OBJECTIVE: To investigate the association between liver enzymes and ovarian cancer (OC), and to validate their potential as biomarkers and their mechanisms in OC. Methods Genome-wide association studies for OC and levels of enzymes such as Alkaline phosphatase (ALP), Aspartate aminotransferase (AST), Alanine aminotransferase, and gamma-glutamyltransferase were analyzed. Univariate and multivariate Mendelian randomization (MR), complemented by the Steiger test, identified enzymes with a potential causal relationship to OC. Single-cell transcriptomics from the GSE130000 dataset pinpointed pivotal cellular clusters, enabling further examination of enzyme-encoding gene expression. Transcription factors (TFs) governing these genes were predicted to construct TF-mRNA networks. Additionally, liver enzyme levels were retrospectively analyzed in healthy individuals and OC patients, alongside the evaluation of correlations with cancer antigen 125 (CA125) and Human Epididymis Protein 4 (HE4). RESULTS: A total of 283 single nucleotide polymorphisms (SNPs) and 209 SNPs related to ALP and AST, respectively. Using the inverse-variance weighted method, univariate MR (UVMR) analysis revealed that ALP (P = 0.050, OR = 0.938) and AST (P = 0.017, OR = 0.906) were inversely associated with OC risk, suggesting their roles as protective factors. Multivariate MR (MVMR) confirmed the causal effect of ALP (P = 0.005, OR = 0.938) on OC without reverse causality. Key cellular clusters including T cells, ovarian cells, endothelial cells, macrophages, cancer-associated fibroblasts (CAFs), and epithelial cells were identified, with epithelial cells showing high expression of genes encoding AST and ALP. Notably, TFs such as TCE4 were implicated in the regulation of GOT2 and ALPL genes. OC patient samples exhibited decreased ALP levels in both blood and tumor tissues, with a negative correlation between ALP and CA125 levels observed. CONCLUSION: This study has established a causal link between AST and ALP with OC, identifying them as protective factors. The increased expression of the genes encoding these enzymes in epithelial cells provides a theoretical basis for developing novel disease markers and targeted therapies for OC.
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Fosfatasa Alcalina , Biomarcadores de Tumor , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Neoplasias Ováricas , Polimorfismo de Nucleótido Simple , Análisis de la Célula Individual , Humanos , Femenino , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Polimorfismo de Nucleótido Simple/genética , Análisis de la Célula Individual/métodos , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/sangre , Biomarcadores de Tumor/genética , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/genética , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/metabolismo , Aspartato Aminotransferasas/genética , Aspartato Aminotransferasas/sangre , Hígado/patología , Hígado/metabolismo , Alanina Transaminasa/sangre , Alanina Transaminasa/genética , gamma-Glutamiltransferasa/genética , gamma-Glutamiltransferasa/sangre , Antígeno Ca-125/genética , Regulación Neoplásica de la Expresión Génica/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas de la Membrana/genética , Persona de Mediana EdadRESUMEN
OBJECTIVE: We recently characterized the clinical performance of a multivariate index assay (MIA3G) to assess ovarian cancer risk for adnexal masses at initial presentation. This study evaluated how MIA3G varies when applied longitudinally to monitor risk during clinical follow-up. METHOD: The study evaluated women presenting with adnexal masses from eleven centers across the US. Patients received an initial blood draw at enrollment and at the standard-of-care follow-up visits. MIA3G was determined for all visits but physicians did not have access to MIA3G scores to determine clinical management. The primary outcome was the relative change value (RCV) of MIA3G over the period of clinical observation. RESULTS: A total of 510 patients of 785 enrolled met study criteria. Of these, 30.8% had a second, 25.4% a third and 22.2% a fourth blood draw following initial collection. The median duration from initial draw was 131 d to second draw, 301.5 d to the third draw and 365.5 d to the fourth draw. MIA3G RCV of >50% was observed in 22-26% patients, whereas 70-75% patients had MIA3G RCV >5%. An empirical baseline RCV of 56% - transformed to 1 in logarithmic scale - was calculated from averaging RCVs of all patients who had no malignancy risk after 210 days. RCV > 1 log was associated with higher incidence of surgical intervention (29.6%) compared to RCV < 1 log (16.9%). CONCLUSIONS: Variation in MI3AG does not change the accuracy of the test for excluding malignancy, while marked changes may be associated with a slightly higher likelihood of surgical intervention. In addition to MIA3G score itself, the MIA3G RCV may be important for clinical management.
Asunto(s)
Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/sangre , Neoplasias Ováricas/diagnóstico , Persona de Mediana Edad , Estudios Longitudinales , Adulto , Anciano , Medición de Riesgo/métodos , Biomarcadores de Tumor/sangre , Análisis Multivariante , Anciano de 80 o más Años , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAPRESUMEN
OBJECTIVE: This study aimed to explore the application value of human epididymis protein 4 (HE4) in diagnosing and monitoring the prognosis of lung cancer. METHODS: First, TCGA (The Cancer Genome Atlas) databases were used to analyze whey-acidic-protein 4-disulfide bond core domain 2 (WFDC2) gene expression levels in lung cancer tissues. Then, a total of 160 individuals were enrolled, categorized into three groups: the lung cancer group (n = 80), the benign lesions group (n = 40), and the healthy controls group (n = 40). Serum HE4 levels and other biomarkers were quantified using an electro-chemiluminescent immunoassay. Additionally, the expression of HE4 in tissues was analyzed through immunohistochemistry (IHC). In vitro cultures of human airway epithelial (human bronchial epithelial [HBE]) cells and various lung cancer cell lines (SPC/PC9/A594/H520) were utilized to detect HE4 levels via western blot (WB). RESULTS: Analysis of the TCGA and UALCAN (The University of Alabama at Birmingham Cancer Data Analysis Portal) databases showed that WFDC2 gene expression levels were upregulated in lung cancer tissues (p < 0.01). Compared with the control group and the benign group, HE4 was significantly higher in the serum of patients with lung cancer (p < 0.001). Receiver operating characteristic (ROC) analysis confirmed that HE4 had better diagnostic efficacy than classical markers in the differential diagnosis of lung cancer and benign lesions and had the highest diagnostic value in lung adenocarcinoma (area under the ROC curve [AUC] = 0.826). HE4 increased in early lung cancer and positively correlated with poor prognosis (p < 0.001). Moreover, the results of WB and IHC revealed that the expression of HE4 was increased in lung cancer cells (SPC/A549/H520) and lung cancer tissues but decreased in PC9 cells with a lack of exon EGFR19 (p < 0.05). CONCLUSION: Serum HE4 emerges as a promising novel biomarker for the diagnosis and prognosis assessment of lung cancer.
Asunto(s)
Biomarcadores de Tumor , Neoplasias Pulmonares , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Inmunohistoquímica , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Pronóstico , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/metabolismo , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/análisisRESUMEN
This study aimed to analyze the relationship between human epididymal protein 4 (HE4) and infiltration depth, postoperative recurrence, and metastasis of epithelial ovarian cancer (OVCA). Immunohistochemistry was used to detect the expression level of HE4 in cancer tissues and adjacent tissues of 90 patients with epithelial OVCA admitted to our hospital from May 2017 to January 2018. Cox regression was used to analyze the factors affecting the prognosis of epithelial OVCA. The relationship between HE4 and the prognosis of epithelial OVCA was analyzed by the receiver operating characteristic curve and Kaplan-Meier survival curve. The positive expression rate of HE4 in epithelial OVCA was 85.56%, which was higher than 34.44% in adjacent tissues (p < 0.01). The International Federation of Gynecology and Obstetrics stage, infiltration depth, lymph node metastasis, postoperative recurrence and metastasis, and HE4 positivity were independent risk factors for the prognosis, and platinum-based chemotherapy sensitivity was an independent protective factor for the prognosis of patients with epithelial OVCA (p < 0.05). The area under the curve of HE4 in diagnosing epithelial OVCA and predicting recurrence was 0.863 and 0.700, the sensitivity was 91.60% and 85.60%, and the specificity was 90.20% and 65.60%. The median progression-free survival and overall survival were 26.1 and 30.2 months in HE4-positive epithelial OVCA patients, while these were 31.4 and 35.6 months in HE4-negative epithelial OVCA patients (p < 0.05). In conclusion, HE4 was highly expressed in epithelial OVCA tissues. Its expression level was related to the depth of tumor invasion, postoperative recurrence and metastasis, and other clinicopathological characteristics of patients with epithelial OVCA.
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Carcinoma Epitelial de Ovario , Invasividad Neoplásica , Recurrencia Local de Neoplasia , Neoplasias Ováricas , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP , Humanos , Femenino , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/metabolismo , Carcinoma Epitelial de Ovario/cirugía , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/análisis , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/metabolismo , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/patología , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/cirugía , Pronóstico , Adulto , Biomarcadores de Tumor/metabolismo , Anciano , Metástasis de la NeoplasiaRESUMEN
BACKGROUND: Human epididymis protein 4 (HE4) has been identified as a biomarker for renal fibrosis. This study aimed to evaluate the role of HE4 in the diagnosis and determination of disease severity and hepatic fibrosis in autoimmune hepatitis (AIH). METHODS: Serum HE4 levels were determined via electrochemiluminescence immunoassays in 60 healthy controls and 109 AIH patients (43 without liver cirrhosis and 66 with liver cirrhosis). Liver biopsy was performed on 56 of 109 enrolled patients. We conducted a 5-year follow-up survey of 53 enrolled patients. All continuous variables were reported as median (25th-75th percentile). RESULTS: Serum HE4 levels were significantly elevated in autoimmune hepatitis with liver cirrhosis (AIH-LC) patients compared with AIH patients and healthy controls [98.60 (74.15-139.08) vs 73.50 (59.88-82.00) vs 48.75 (43.38-52.93) pmol/L, p = 0.004]. The serum HE4 levels showed a positive correlation with the METAVIR scoring system in patients with liver biopsy (r = 0.711, p < 0.001). Serum HE4 levels were significantly elevated in Child-Pugh class C patients compared with Child-Pugh class B patients and Child-Pugh class A patients [106.50 (83.46-151.25) vs 110.00 (73.83-166.75) vs 77.03 (72.35-83.33) pmol/L, p = 0.006]. The diagnostic sensitivity and specificity of serum HE4 for evaluating liver cirrhosis were 69.7 % and 79.07 %, respectively, with a cutoff value of 82.34 pmol/L in enrolled patients. The logistic regression analysis showed that high levels of HE4 (≥82.34 pmol/L) were associated with AIH-LC (OR = 8.751, 95 % CI = 1.412-54.225, p = 0.020). The Kaplan-Meier curves demonstrated that high levels of serum HE4 (≥82.34 pmol/L) were associated with poor outcome (log-rank p = 0.037, HR = 0.372, 95 % CI = 0.146-0.946). CONCLUSIONS: Serum HE4 levels were found to be elevated in AIH-LC patients and exhibited a strong correlation with the severity of hepatic fibrosis, thus supporting their potential clinical value as a novel biomarker of disease severity and hepatic fibrosis in AIH.
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Biomarcadores , Hepatitis Autoinmune , Cirrosis Hepática , Índice de Severidad de la Enfermedad , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP , Humanos , Cirrosis Hepática/sangre , Cirrosis Hepática/diagnóstico , Biomarcadores/sangre , Masculino , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/análisis , Femenino , Persona de Mediana Edad , Hepatitis Autoinmune/sangre , Hepatitis Autoinmune/diagnóstico , Hepatitis Autoinmune/complicaciones , AdultoRESUMEN
AIM: To develop a new algorithm for the detection of high-grade serous ovarian cancer (HGSOC). METHODS: Patients diagnosed with HGSOC, borderline ovarian tumours (BOTs) or benign ovarian masses (BOMs) were enrolled between February 2019 and December 2020. Patients with BOTs or BOMs were grouped as non-HGSOC. The cases were divided randomly into a training cohort (two-thirds of cases) and a validation cohort (one-third of cases). Logistic regression was used to find risk factors for HGSOC and to create a new algorithm in the training cohort. Receiver operating characteristic curves were used to compare the diagnostic value of tumour biomarkers. Sensitivity and specificity of tumour markers and the new algorithm were calculated in the training cohort and validation cohort. RESULTS: This study found significant differences in age; BRCA1/2 mutation status; CA125, CA724 and HE4 levels; and Risk of Ovarian Malignancy Algorithm score between the two groups.Logistic regression analysis showed that CA125 and BRCA1/2 were risk factors for HGSOC. A new algorithm combining CA125 and BRCA1/2 increased the specificity of CA125 for diagnosis of HGSOC. The new algorithm had sensitivity of 81.08% and specificity of 93.10% in the training cohort. CONCLUSION: The new algorithm using CA125 and BRCA1/2 helped to distinguish between patients with HGSOC and patients with non-HGSOC.
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Algoritmos , Biomarcadores de Tumor , Antígeno Ca-125 , Neoplasias Ováricas , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP , Humanos , Femenino , Antígeno Ca-125/sangre , Neoplasias Ováricas/sangre , Neoplasias Ováricas/diagnóstico , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/análisis , Persona de Mediana Edad , Adulto , Biomarcadores de Tumor/sangre , Antígenos de Carbohidratos Asociados a Tumores/sangre , Cistadenocarcinoma Seroso/sangre , Cistadenocarcinoma Seroso/diagnóstico , Anciano , Sensibilidad y Especificidad , Factores de Riesgo , Proteínas de la Membrana/sangreRESUMEN
OBJECTIVES: This study aimed to assess the diagnostic value of human epididymal protein 4 (HE4), a potential novel biomarker for lung cancer, and its combined detection with five other conventional biomarkers in lung cancer diagnosis and subtyping. METHODS: In this retrospective study, 115 lung cancer patients, 50 patients with benign pulmonary disease, and 50 healthy controls were included. Serum HE4, progastrin-releasing peptide (ProGRP), squamous cell carcinoma (SCC) antigen, cytokeratin-19 fragment (CYFRA21-1), neuron-specific enolase (NSE), and carcinoembryonic antigen (CEA) were analyzed using the electrochemiluminescence immunoassay and chemiluminescence immunoassay. The receiver operating characteristic curve was performed to analyze the diagnostic efficacy of individual biomarkers in identifying both lung cancer and its histologic subtypes. RESULTS: All six biomarkers showed significantly elevated levels in the lung cancer group compared to both benign pulmonary disease and control groups (P < 0.05). Among the biomarkers evaluated, HE4 exhibited the highest diagnostic performance for lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma with area under the curve (AUC) values of 0.921, 0.891, and 0.937, respectively. ProGRP was the optimal biomarker for small cell lung cancer with an AUC of 0.973. The combination of all six biomarkers yielded the largest AUCs in the diagnosis of lung cancer subtypes (0.937 for lung adenocarcinoma, 0.998 for lung squamous cell carcinoma, and 0.985 for small cell lung cancer). Furthermore, specific combinations, such as HE4 + CEA, HE4 + SCC, and ProGRP + HE4 + NSE, showed strong diagnostic performance in lung cancer. CONCLUSIONS: HE4 and its combined detection held substantial clinical significance in the diagnosis of lung cancer and its histologic subtyping, especially for lung adenocarcinoma and lung squamous cell carcinoma.
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Biomarcadores de Tumor , Neoplasias Pulmonares , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/diagnóstico , Estudios Retrospectivos , Masculino , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/metabolismo , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/análisis , Femenino , Persona de Mediana Edad , Biomarcadores de Tumor/sangre , Anciano , Adulto , Carcinoma de Células Escamosas/sangre , Carcinoma de Células Escamosas/diagnóstico , Proteínas/análisis , Proteínas/metabolismo , Fragmentos de Péptidos , Proteínas RecombinantesRESUMEN
Rationale: Bronchiectasis is a pathological dilatation of the bronchi in the respiratory airways associated with environmental or genetic causes (e.g., cystic fibrosis, primary ciliary dyskinesia, and primary immunodeficiency disorders), but most cases remain idiopathic. Objectives: To identify novel genetic defects in unsolved cases of bronchiectasis presenting with severe rhinosinusitis, nasal polyposis, and pulmonary Pseudomonas aeruginosa infection. Methods: DNA was analyzed by next-generation or targeted Sanger sequencing. RNA was analyzed by quantitative PCR and single-cell RNA sequencing. Patient-derived cells, cell cultures, and secretions (mucus, saliva, seminal fluid) were analyzed by Western blotting and immunofluorescence microscopy, and mucociliary activity was measured. Blood serum was analyzed by electrochemiluminescence immunoassay. Protein structure and proteomic analyses were used to assess the impact of a disease-causing founder variant. Measurements and Main Results: We identified biallelic pathogenic variants in WAP four-disulfide core domain 2 (WFDC2) in 11 individuals from 10 unrelated families originating from the United States, Europe, Asia, and Africa. Expression of WFDC2 was detected predominantly in secretory cells of control airway epithelium and also in submucosal glands. We demonstrate that WFDC2 is below the limit of detection in blood serum and hardly detectable in samples of saliva, seminal fluid, and airway surface liquid from WFDC2-deficient individuals. Computer simulations and deglycosylation assays indicate that the disease-causing founder variant p.Cys49Arg structurally hampers glycosylation and, thus, secretion of mature WFDC2. Conclusions: WFDC2 dysfunction defines a novel molecular etiology of bronchiectasis characterized by the deficiency of a secreted component of the airways. A commercially available blood test combined with genetic testing allows its diagnosis.
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Bronquiectasia , Pólipos Nasales , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Bronquiectasia/genética , Bronquiectasia/fisiopatología , Pólipos Nasales/genética , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAPRESUMEN
BACKGROUND: Human epididymis protein 4 (HE4) is a tumor marker overexpressed in ovarian cancer and is commonly utilized to aid with diagnosis of an adnexal mass. HE4 levels vary based on pregnancy, age, menopausal status, and tobacco use. OBJECTIVE(S): The objective of this study was to evaluate population-based data to examine factors that affect HE4 among adult women in the United States and stratify levels of HE4 by demographic and gynecologic factors. STUDY DESIGN: A retrospective analysis was conducted using data from 2,480 women aged 20 + who participated in the National Health and Nutrition Examination Survey (2001-2002). From these cross-sectional data, serum HE4 and cotinine, a marker of tobacco exposure, were combined with demographic and interview data. Estimated glomerular filtration rates (eGFR) were based on serum creatinine, age, sex, and race. Other variables of interest included menopausal status, pregnancy, and various gynecologic factors. Summary HE4 data are provided as geometric means with associated 95 % confidence intervals. RESULTS: HE4 levels were independently associated with age, renal function, and nicotine use, all p < 0.001. Pre-menopausal women with a history of endometriosis were found to have elevated HE4 levels compared to those without, p < 0.01; however, we found no such difference among post-menopausal women. Adjusting for age, no differences in HE4 were found based on race/ethnicity, p = 0.29. HE4 levels showed statistically significant associations with income level; however, these were small and clinically irrelevant. CONCLUSION: This study provides evaluation of HE4 levels among a data set representative of 98.5 million non-institutionalized women in the United States and gives insight into extraneous factors that may influence these levels.
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Encuestas Nutricionales , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP , Humanos , Femenino , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/análisis , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/metabolismo , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Estados Unidos/epidemiología , Estudios Transversales , Proteínas/análisis , Proteínas/metabolismo , Adulto Joven , Embarazo , Anciano , Menopausia/sangre , Factores de EdadRESUMEN
OBJECTIVE: To assess the feasibility of scalable, objective, and minimally invasive liquid biopsy-derived biomarkers such as cell-free DNA copy number profiles, human epididymis protein 4 (HE4), and cancer antigen 125 (CA125) for pre-operative risk assessment of early-stage ovarian cancer in a clinically representative and diagnostically challenging population and to compare the performance of these biomarkers with the Risk of Malignancy Index (RMI). METHODS: In this case-control study, we included 100 patients with an ovarian mass clinically suspected to be early-stage ovarian cancer. Of these 100 patients, 50 were confirmed to have a malignant mass (cases) and 50 had a benign mass (controls). Using WisecondorX, an algorithm used extensively in non-invasive prenatal testing, we calculated the benign-calibrated copy number profile abnormality score. This score represents how different a sample is from benign controls based on copy number profiles. We combined this score with HE4 serum concentration to separate cases and controls. RESULTS: Combining the benign-calibrated copy number profile abnormality score with HE4, we obtained a model with a significantly higher sensitivity (42% vs 0%; p<0.002) at 99% specificity as compared with the RMI that is currently employed in clinical practice. Investigating performance in subgroups, we observed especially large differences in the advanced stage and non-high-grade serous ovarian cancer groups. CONCLUSION: This study demonstrates that cell-free DNA can be successfully employed to perform pre-operative risk of malignancy assessment for ovarian masses; however, results warrant validation in a more extensive clinical study.
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Biomarcadores de Tumor , Neoplasias Ováricas , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP , Humanos , Femenino , Neoplasias Ováricas/sangre , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/cirugía , Neoplasias Ováricas/patología , Estudios de Casos y Controles , Persona de Mediana Edad , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/análisis , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/metabolismo , Biopsia Líquida/métodos , Biomarcadores de Tumor/sangre , Ácidos Nucleicos Libres de Células/sangre , Adulto , Anciano , Antígeno Ca-125/sangreRESUMEN
OBJECTIVE: To determine the relationship between pre-operative HE4 and CA125 levels in non-mucinous epithelial ovarian cancer cases (EOC) and outcomes of primary surgery for prediction of optimal surgery. METHODS: A retrospective study was performed on non-mucinous EOC who underwent primary surgery at King Chulalongkorn Memorial Hospital from 2016 to 2020. Demographic and clinical characters were collected. Histopathology and pre-operative tumor markers namely HE4 and CA125 were also recruited. Primary surgical outcomes were classified as optimal (OS) and suboptimal surgery (SS). RESULTS: One hundred and seventy patients were enrolled in the study. There were 130 and 40 cases in OS and SS, respectively. Average age and body mass index (BMI) of EOC were 54.2 years old and 23.1 Kg/m2, respectively. Both groups had comparable demographic characteristics. Two-thirds (103/170) and one-third (63/170) had early stage and clear cell histopathology, respectively. The median level of HE4 were 118.60 and 603.45 pmol/L in OS and SS, respectively. OS and SS had average CA125 at 146.95 and 814.70 U/L, respectively. The best cut-off point of HE4 and CA125 less than 170.95 pmol/L and 316.4 U/mL gave predicting OS with area under curve (AUC) at 0.78 and 0.75, respectively. HE4 and CA125 cut-off point had sensitivity, specificity, positive predict value (PPV) and negative predictive value (NPV) at percentage of 60.8/60.8, 87.5/82.5, 94.1/91.9 and 40.7/39.3, respectively. CONCLUSION: HE4 and CA125 of non-mucinous EOC among OS had significantly less than SS and could be the predicting of optimal surgery.