The Role of Human Epididymis Protein 4 in the Diagnosis and Prognosis of Diseases: An Umbrella Review of Systematic Reviews and Meta-Analyses of Observational Studies

Abstract

BackgroundThe application of human epididymis protein 4 (HE4) in diverse health diseases, especially in cancers, has been extensively studied in recent decades. To summarize the existing evidence of the aforementioned topic, we conducted an umbrella review to systematically evaluate the reliability and strength of evidence regarding the role of HE4 in the diagnostic and prognostic estimate of diverse diseases.MethodsElectronic searches in PubMed, Web of Science, and Embase databases were conducted from inception to September 16, 2021, for meta-analyses, which focus on the role of HE4 in the diagnosis and prognosis of diseases. This study protocol has been registered at PROSPERO (CRD42021284737). We collected the meta-analysis effect size of sensitivity, specificity, positive predictive value, and negative predictive value from diagnostic studies and gathered the hazard ratio (HR) of disease-free survival, overall survival, and progression-free survival from prognostic studies. For each systematic review and meta-analysis, we used a measurable tool for evaluating systematic reviews and meta-analysis (AMSTAR) to evaluate the methodological quality. Additionally, we assessed the quality of evidence on estimating the ability of HE4 in the diagnosis and prognosis of diverse diseases by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guideline.ResultsOverall, 20 meta-analyses including a total of 331 primary studies of different diseases were examined, mainly including ovarian cancer (OC) (n = 9), endometrial cancer (EC) (n = 6), and lung cancer (LC) (n = 4). The methodological qualities of all studies were rated as moderate (45%) or high (55%) by the AMSTAR. According to the GRADE, the certainties of 18 diagnostic pieces of evidence (9 for sensitivity and 9 for specificity) were rated as moderate (34%), low (33%), and very low (33%). Moreover, outcomes from prognosis studies showed evidence (1 for disease-free survival) with high certainty in regard to cancers (such as EC, OC, and LC) with the remaining three being moderate.ConclusionThis umbrella review suggested that HE4 was a favored biomarker in the prognosis of cancers, which was supported by high certainty of evidence. Additionally, HE4 could provide a suitable method for the diagnosis of EC, OC, and LC with moderate certainty evidence. Further large prospective cohort studies are needed to better elucidate the diagnostic and prognostic role of HE4 in diseases.

Human epididymis protein 4, a novel potential biomarker for diagnostic and prognosis monitoring of lung cancer

“…Scholars Sun and Mo have reported that lung cancer patients with high HE4 levels have significantly shorter survival times than those with lower levels 28,29 . We conducted a RECIST 1.1 assessment on the treated patients and found that the HE4 levels in the PD group were significantly higher than those of patients in the CR, PR, and SD groups, which confirmed our conjecture and also showed that HE4 can be used as a prognostic monitoring indicator for lung cancer 28 . Furthermore, the serum levels of HE4 in the lung cancer cohort were not influenced by smoking or gender, aligning with the literature 14,15,29,30 .…”

“…Simultaneously, we observed a significant increase in HE4 levels in patients with advanced disease (stages III–IV), speculating that elevated HE4 expression may be an important feature of lung cancer progression. Scholars Sun and Mo have reported that lung cancer patients with high HE4 levels have significantly shorter survival times than those with lower levels 28,29 . We conducted a RECIST 1.1 assessment on the treated patients and found that the HE4 levels in the PD group were significantly higher than those of patients in the CR, PR, and SD groups, which confirmed our conjecture and also showed that HE4 can be used as a prognostic monitoring indicator for lung cancer 28 .…”

“… 28 , 29 We conducted a RECIST 1.1 assessment on the treated patients and found that the HE4 levels in the PD group were significantly higher than those of patients in the CR, PR, and SD groups, which confirmed our conjecture and also showed that HE4 can be used as a prognostic monitoring indicator for lung cancer. 28 Furthermore, the serum levels of HE4 in the lung cancer cohort were not influenced by smoking or gender, aligning with the literature. 14 , 15 , 29 , 30 The reason may be that the impact of lung cancer progression on HE4 covers gender and subtle changes produced by smoking.…”

Special Issue “Ovarian Cancer: Advances on Pathophysiology and Therapies”

“…In addition to these insightful research articles, two reviews in this Special Issue highlight the role of the solute carrier family 7 member 11 (SLC7A11) transporter (reviewed by Fantone and colleagues) and human epididymis protein 4 (HE4) (reviewed by Anastasi and colleagues) in ovarian cancer, two important players involved in ferroptosis modulation (SLC7A11) [26,27] and ovarian cancer detection (HE4) [28][29][30], respectively. Another review by Vorderbruggen and colleagues highlighted the role of proteolysis targeting chimeras (PROTACs) in ovarian cancer, reviewing the pharmacodynamic properties of these agents.…”

Editorial: Molecular markers in rheumatic diseases and their comorbidities

“…This constitutes a real challenge to clinicians because, in addition to managing SARD, they have to offer adequate control of comorbidities in a multidisciplinary setting with the aim of improving the quality of life of their patients ( 9 ). Liang et al showed elevated levels of human epididymis protein 4 (HE 4 ), a protein expressed in several tissues and used as a biomarker in ovarian cancer ( 10 ), in patients with rheumatoid arthritis (RA) compared to healthy subjects; those who were positive for HE 4 had a higher prevalence of interstitial lung disease (ILD); these data are the first to identify a correlation between HE 4 levels and ILD.…”