Exploring Nectin-4 as a potential diagnostic biomarker in endometrial adenocarcinoma

Background This study explored Nectin-4 expression in endometrial adenocarcinoma and examined its relationship with tumor grade, hormone receptor status, p53 expression, and mismatch repair (MMR) protein expression.

We retrospectively analyzed 55 paraffin-embedded tissue samples collected between 2015 and 2023, including endometrial adenocarcinoma, endometrial intraepithelial neoplasia (EIN), and normal endometrium samples. Nectin-4 expression was assessed via immunohistochemistry, and correlations with clinicopathological features and molecular markers were evaluated statistically.

Nectin-4 expression increased with histological grade (p < 0.001). All Grade III tumors presented strong expression, whereas lower-grade tumors presented variable staining. The expression of these genes was also correlated with p53 overexpression (p = 0.007) and PMS2 loss (p = 0.002). Nectin-4 was absent in normal tissues and weakly expressed in EIN.

Nectin-4 expression is linked to high-grade endometrial carcinoma and abnormal p53 expression, supporting its potential role as a diagnostic biomarker. Larger studies are needed to validate its clinical use. Similar content being viewed by others

Endometrial adenocarcinoma is the most common gynecological cancer in developed countries and remains a major health burden worldwide [1]. Endometrial cancers are traditionally divided into two groups. Type I tumors, which are mainly endometrioid adenocarcinomas, make up approximately 80% of cases. They are often estrogen-dependent and associated with favorable outcomes, MSI, or PTEN mutations [2]. Type II tumors, such as serous carcinomas, are less common but more aggressive and typically harbor p53 mutations and chromosomal instability [3]. Molecular classifications have refined risk assessment. The Cancer Genome Atlas (TCGA) describes four subtypes: POLE ultramutated, MSI-high, p53-abnormal (copy number high), and p53-wild type (copy number low), each with different prognostic implications [4]. The ProMisE classifier translates these into clinically useful categories, focusing on MMR deficiency, POLE mutations, and p53 abnormalities [5]. Nevertheless, variability within groups highlights the need for additional biomarkers [6]. Cell adhesion molecules have recently been investigated for their role in invasion, metastasis, and immune escape [7]. Nectin-4, a member of this family, is overexpressed in several cancers, including breast, ovarian, pancreatic, and urothelial tumors [8, 9]. Its presence is correlated with advanced disease, aggressiveness, and poor survival, highlighting its value as both a biomarker and a therapeutic target [10, 11]. In gynecologic cancers, Nectin-4 has been linked to higher grade, abnormal p53 expression, and MMR deficiency [12, 13]. Because it is a cell surface protein, it is also a promising target for therapies such as enfortumab vedotin, an antibody–drug conjugate already in clinical use for bladder cancer [14]. Thus, we investigated Nectin-4 expression in endometrial adenocarcinoma and its relationship with tumor grade, p53 status, and MMR proteins.

We analyzed 55 paraffin-embedded tissue samples collected between 2015 and 2023. The cases included 35 endometrioid endometrial adenocarcinomas (17 grade 1, 10 grade 2, and 8 grade 3), 10 EIN cases, and 10 normal endometrium samples. All histological diagnoses and grades were confirmed by a pathologist. Section (4 μm thick) were stained with a primary anti–Nectin-4 antibody (clone ab192033, Abcam, Cambridge, UK; dilution 1:200) using an automated immunostainer (VENTANA Discovery XT, Ventana Medical Systems, Tucson, AZ, USA). The same platform and detection system were also applied for other markers, including anti-p53 (clone Bp53-11), MLH1 (clone M1), PMS2 (clone G219-1129), MSH2 (clone SP93), MSH6 (clone A16-4), ER (clone 4B5), and PR (clone 1E2). OptiView DAB IHC v4 software together with the OptiView DAB IHC Detection Kit (Ventana Medical Systems) and amplification reagents were used. Antigen retrieval was performed with Cell Conditioning Solution 2 (CC2, Ventana) for 32 min. A universal linker and horseradish peroxidase (HRP) multimer were applied for 8 min each, followed by an OptiView Amplifier and amplification multimer for 4 min each. Hematoxylin was used for counterstaining. Urothelial carcinoma tissue served as the positive control. All molecular markers, including p53, MMR proteins (MLH1, MSH2, MSH6, and PMS2), estrogen receptor (ER), and progesterone receptor (PR), were evaluated immunohistochemically on formalin-fixed, paraffin-embedded tissue sections. ER, PR, p53, and MMR assessments were re-evaluated by retrieving the diagnostic slides from the pathology archive, and all tumors were confirmed to be POLE mutation–negative. Immunohistochemical evaluation of Nectin-4 expression was performed by an experienced independent pathologist who was blinded to all clinical data. The intensity and proportion of positively stained tumor cells were semi-quantitatively assessed. The H-score was calculated as the product of staining intensity (0–3) and percentage of positive cells (0–100). Staining was graded as 0 (negative), 1+ (weak), 2+ (moderate), or 3+ (strong). H score = Σ (staining intensity × percentage of positive cells). Molecular Markers: - 1. p53: wild-type (scattered) or mutant-like (overexpressed/absent). - 2. Mismatch repair (MMR) deficiency was defined as the complete loss of nuclear staining in tumor cells for any of the four MMR proteins (MLH1, PMS2, MSH2, MSH6), in the presence of positive internal control in non-neoplastic cells. Tumors showing abnormal strong diffuse p53 staining or complete absence of p53 staining were categorized as p53-aberrant, whereas those with weak, heterogeneous nuclear staining were classified as p53-wild type. - 3. ER and PR: positive if ≥ 1% nuclear staining was detected. Statistical analyses were performed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). The Spearman correlation test was used to evaluate relationships between Nectin-4 expression, tumor grade, and p53 status; a p-value < 0.05 was considered statistically significant. Categorical variables were compared using the chi-square test or Fisher’s exact test, as appropriate. Continuous variables were analyzed using the Kruskal–Wallis and Mann–Whitney U tests. Since no prior study has reported power estimates for Nectin-4 expression in endometrial adenocarcinoma, a post hoc power analysis was conducted. Based on the observed association between Nectin-4 expression and histological grade, Cohen’s w was calculated as 0.75, indicating a large effect size. With α = 0.05, a minimum of 20 cases yields approximately 90% statistical power. Our dataset of 55 cases provided > 95% power, confirming the robustness of the study findings.

A total of 55 cases were included in this study, consisting of 35 endometrioid carcinomas, 10 EIN lesions, and 10 non-neoplastic endometrial tissues. All tumors were of the endometrioid subtype; no serous, clear cell, or mixed histology was included. The mean patient age was 59.2 ± 8.7 years (range, 41–78). Correlations between Nectin-4 expression and molecular markers are summarized in Table 1. Nectin-4 positivity was significantly associated with p53 aberrance (p = 0.007) and PMS2 loss (p = 0.002), whereas no significant associations were observed with MLH1, MSH2, or MSH6 (p > 0.05). MMR deficiency was identified in 14 of 35 carcinomas (40%), and abnormal p53 expression in 12 of 35 carcinomas (34%). Among MMR-deficient tumors, isolated PMS2 loss was subclonal in five cases, MLH1 hypermethylation was confirmed in two cases, and three patients declined methylation testing. This association is further illustrated in Fig. 1, which shows p53 mutant-type staining and strong Nectin − 4 expression within the same tumor section, along with the corresponding H&E image, confirming their co-expression pattern. No confirmed Lynch syndrome was identified. When the four MMR proteins were analyzed collectively as MMR-deficient (MMRd), Nectin-4 expression remained significantly higher in the MMRd group (p = 0.01). In the tumor group, concurrent loss of both MLH1 and PMS2 was observed in only two cases. These two cases demonstrated MLH1 promoter hypermethylation and were therefore not considered indicative of Lynch syndrome. In cases showing isolated PMS2 loss, immunohistochemical evaluation was performed on curettage materials, and the pathology reports recommended repeating the analysis on excisional specimens. Final pathology reports revealed that MLH1 loss was absent in eight cases, while PMS2 loss was subclonal in five cases. Three patients declined methylation testing, and final reports for the remaining cases were not accessible. One case demonstrated concurrent loss of MSH2 and MSH6, and the patient was referred for genetic testing; however, the findings were not consistent with Lynch syndrome. Two additional cases with isolated MSH6 loss exhibited p53-aberrant (mutant-type) staining and were classified as p53-aberrant molecular subtype. In the primary curettage materials of these cases, MSH6 loss was observed in a subclonal and predominantly cytoplasmic pattern. Nectin-4 immunoreactivity was observed in 31 of 35 carcinomas (88.6%), 4 of 10 EIN lesions (40%), and 2 of 10 non-neoplastic endometrial samples (20%). Mean H-scores increased significantly with histological grade (Grade 1: 82 ± 15; Grade 2: 145 ± 22; Grade 3: 255 ± 30; p < 0.001). As shown in Table 2, Nectin-4 expression increased progressively with histologic grade (p < 0.001), supporting its association with tumor dedifferentiation. Spearman’s correlation analysis confirmed that Nectin-4 expression correlated positively with tumor grade (ρ = 0.61, p < 0.01) and with p53 status (ρ = 0.55, p < 0.01). Table 3 summarizes clinicopathologic parameters, including age, tumor grade distribution, ER and PR status, p53 status, and MMR status. ER and PR were positive in all carcinoma cases. Because the study was based primarily on curettage specimens, parameters such as FIGO stage at hysterectomy, depth of myometrial invasion, and lymphovascular space invasion (LVSI) could not be assessed. However, in 15 cases with available excisional specimens, the diagnoses were concordant and the Nectin-4 staining pattern was consistent between the curettage and the excisional specimen, supporting the reliability of curettage-based evaluation. Representative immunohistochemical images illustrate weak (Fig. 2), moderate (Fig. 3), and strong (Fig. 4) Nectin-4 staining in endometrioid carcinoma. Strong Nectin-4 staining was most frequent in Grade 3 tumors (87.5%), whereas Grade 1–2 tumors showed weaker expression (p = 0.002). Figures 5 and 6 demonstrate MMR protein expression, with Fig. 5 showing intact nuclear staining and Fig. 6 showing complete loss of expression in tumor cells. All p53-aberrant tumors were strongly positive for Nectin-4 (p = 0.007), and PMS2 loss was significantly associated with high Nectin-4 expression (64.3%, p = 0.002), whereas no significant associations were observed with MLH1, MSH2, or MSH6 (p > 0.05). PMS2 loss also correlated with higher histological grade (p = 0.002).Nectin-4 expression increased with age (p < 0.001, r = 0.62).

Endometrial cancers are heterogeneous, with variations in molecular and clinical behavior [1, 4, 5]. Current classifications, including TCGA and ProMisE, have improved risk stratification but still leave gaps [4,5,6]. Our study provides evidence that Nectin-4 expression, which is absent in the normal endometrium and EIN, increases sharply in high-grade tumors, supporting its role as a marker of aggressiveness [9, 10]. The primary objective of our study was to evaluate the potential diagnostic value of Nectin-4 expression in curettage materials, particularly in cases where the distinction between atypical endometrial hyperplasia (EIN) and well-differentiated endometrioid carcinoma can be challenging. Identifying a biomarker that could facilitate early diagnosis in limited tissue samples may improve patient outcomes by allowing timely treatment decisions. Serous carcinomas were deliberately excluded because they have distinct histopathological and molecular features that rarely overlap with endometrioid carcinomas or atypical hyperplasia and therefore do not contribute to this diagnostic context. High Nectin-4 has been linked to poor survival in patients with breast, urothelial, pancreatic, and ovarian cancers [11,12,13,14,15]. Meta-analyses confirm its broad prognostic value [10, 16]. As a surface protein, it is also an attractive therapeutic target [14, 17]. TP53 mutations are frequent in high-grade endometrial carcinoma [18,19,20]. These tumors behave aggressively and respond poorly to therapy [20]. Our data revealed that all p53-abnormal tumors also strongly expressed Nectin-4, suggesting an interaction between adhesion molecules and the p53 pathway [21]. This aligns with findings in ovarian and bladder cancers [22, 23]. Such tumors may represent a particularly aggressive subgroup. MMR deficiency drives MSI, a hallmark of Lynch syndrome [4, 12]. Approximately 20–30% of sporadic tumors are MSI-high, mostly due to MLH1 promoter hypermethylation [24]. Since MLH1 and PMS2 form a heterodimer, MLH1 loss usually results in PMS2 loss. Although isolated PMS2 loss is typically considered a red flag for Lynch syndrome, the penetrance of PMS2 mutations is low and family history may not always be informative. Somatic mutation in the PMS2 gene may develop as a result of damage to both alleles of PMS2 in the tumor’s DNA.In this case, Lynch syndrome is not necessarily present. PMS2 loss has been reported only infrequently in many published series; however, its detection rate increases when immunohistochemistry is performed with optimized protocols and when subclonal or focal loss is carefully reviewed. In our study, PMS2 staining was specifically optimized and slides were examined in detail, which may partially explain the higher number of isolated PMS2-loss cases identified. All tumors showing concurrent MLH1/PMS2 loss underwent MLH1 promoter methylation testing, confirming sporadic MMR deficiency rather than Lynch syndrome. For cases with isolated PMS2 loss, internal positive controls and additional technical checks were used to exclude artefactual staining [25, 26]. We found that PMS2 loss was correlated with high Nectin-4 expression, supporting reports that Nectin-4 is enriched in MMR-deficient cancers [12]. These findings suggest that Nectin-4 may contribute to immune evasion in MSI-high tumors [27]. IHC for MSI is already widely used [14], and adding Nectin-4 could refine risk assessment. As isolated PMS2 loss also signals Lynch syndrome [28], the integration of Nectin-4 may provide insights into hereditary risk and therapeutic vulnerabilities. All tumors showing concurrent MLH1/PMS2 loss underwent MLH1 promoter methylation testing, confirming sporadic MMR deficiency rather than Lynch syndrome. For cases with isolated PMS2 loss, internal positive controls and additional technical checks were used to exclude artefactual staining. Nectin-4 is already targeted in bladder cancer patients with enfortumab vedotin [29]. Our findings support the use of similar strategies in endometrial carcinoma. Combination with immunotherapy may be especially effective in MMR-deficient tumors [30]. Emerging evidence suggests that Nectin-4 positivity could predict the response to ADC therapy [31]. Ongoing studies are exploring mechanisms of resistance, such as ABC transporters [32]. In our cohort, parameters such as FIGO stage, myometrial invasion, and LVSI could not be evaluated because the study was based primarily on curettage specimens. However, in 15 patients with available excisional materials, both the histopathologic diagnosis and Nectin-4 staining pattern were fully concordant with the curettage findings, supporting the reliability of Nectin-4 evaluation in initial diagnostic samples. This retrospective, single-institution study has modest sample size and limited follow-up. Nevertheless, these findings highlight the potential diagnostic, and therapeutic role of Nectin-4. Future prospective studies should explore the mechanisms linking the Nectin-4, p53, and MMR pathways [33]. Trials of Nectin-4–directed therapies in gynecologic cancers are warranted [32,33,34,35,36], and such approaches may also contribute to broader innovations in gynecological cancer management [36].

Nectin-4 expression increases with tumor grade and is correlated with p53 overexpression and PMS2 loss in endometrial adenocarcinoma. It shows promise as a potential therapeutic target. Larger, multicenter studies are needed to confirm these findings and explore Nectin-4–directed strategies in high-risk patients. Data availability The datasets generated and analyzed during the current study are not publicly available due to institutional restrictions and patient confidentiality, but are available from the corresponding author on reasonable request. Abbreviations - ADC: - Antibody–Drug Conjugate - CC2: - Cell Conditioning Solution 2 - DNA: - Deoxyribonucleic Acid - EIN: - Endometrial Intraepithelial Neoplasia - ER: - Estrogen Receptor - FFPE: - Formalin-Fixed, Paraffin-Embedded - FIGO: - International Federation of Gynecology and Obstetrics - HRP: - Horseradish Peroxidase - IHC: - Immunohistochemistry - MMR: - Mismatch Repair - MSI: - Microsatellite Instability - MSH2/MSH6: - MutS Homolog 2/6 - MLH1: - MutL Homolog 1 - PMS2: - Postmeiotic Segregation Increased 2 - POLE: - DNA Polymerase Epsilon - PR: - Progesterone Receptor - ProMisE: - Proactive Molecular Risk Classifier for Endometrial Cancer - SPSS: - Statistical Package for the Social Sciences - TCGA: - The Cancer Genome Atlas - TP53: - Tumor Protein p53

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Not applicable. Funding None. Author information Authors and Affiliations Contributions SOG conceived and designed the study, interpreted the data, and drafted the manuscript. MO contributed to data collection, evaluation, and statistical analysis. Both authors reviewed and revised the manuscript critically for important intellectual content. All authors approved the submitted version of the manuscript and agree to be accountable for their own contributions as well as for ensuring the accuracy and integrity of the work. Corresponding author Ethics declarations Ethics approval and consent to participate The Aksaray University Clinical Research Ethics Committee approved this study (Decision No: 2022/18 − 04). The study followed the Declaration of Helsinki. Written informed consent was obtained from all participants. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. About this article Cite this article Ordu, M., Genc, S.O. Exploring Nectin-4 as a potential diagnostic biomarker in endometrial adenocarcinoma. BMC Women's Health 26, 46 (2026). https://doi.org/10.1186/s12905-025-04227-8 Received: Accepted: Published: Version of record: DOI: https://doi.org/10.1186/s12905-025-04227-8