Clinical importance of E‑cadherin deficiency in resectable gastric cancer: A nested case‑control study
- Authors:
- Published online on: July 4, 2025 https://doi.org/10.3892/ol.2025.15173
- Article Number: 427
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Copyright: © Zheng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
The latest global cancer data released by the World Health Organization's International Agency for Research on Cancer in 2020 revealed that gastric cancer (GC) ranks as the fifth most common cancer and the fourth leading cause of cancer-associated mortalities worldwide (1). The occurrence of GC is the result of the long-term effects of a variety of factors, such as Helicobacter pylori infection, diet, smoking and family history. There are obvious regional differences in GC, with the main high-end regions being East Asia, Eastern Europe and some Latin American countries. Notably, China stands out as an area with a high incidence of GC, with projections indicating ~10 million new GC cases and 5.6 million associated deaths between 2021 and 2035 (2). In the United States, the 5-year overall age-standardized relative survival rates of patients with GC were 38.3% (2007–2011), 40.6% (2012–2016) and 42.9% (2017–2021) (3). Despite progress in GC diagnosis and treatment, such as use of the gold-standard gastroscopy treatment and biopsy pathology, the patient prognosis remains unsatisfactory.
GC invasion and metastasis represent the primary causes of mortality. In various malignancies, such as breast cancer and nasopharyngeal carcinoma, epithelial-mesenchymal transition (EMT)-mediated reduction in cell-cell adhesion and enhanced migration properties serve a pivotal role in promoting tumor invasion and migration (3–7). Downregulation of E-cadherin, a key epithelial cell adhesion molecule, has been implicated in enhancing EMT occurrence (8). Decreased E-cadherin expression in breast cancer has been associated with a worse prognosis (9). Notably, while E-cadherin deficiency in patients with GC is relatively low and there are limited related reports, GC is associated with mutations in the E-cadherin gene (CDH1), characterizing hereditary diffuse GC (HDGC), which accounts for 1–2% of GC cases (10). Therefore, the present single-center study aimed to investigate the association between E-cadherin expression and the prognosis of patients with GC.
Patients and methods
Clinical data
A total of 1,574 patients with GC who underwent radical gastrectomy at Ningbo No. 2 Hospital (Ningbo, China) between January 2013 and December 2022 were included in the present study. Among them, the number of men was 1,103 and the number of women was 471. The age ranged from 23 to 92 years, with a median age of 66 years. It is notable that clinical subjects were opportunistically recruited in the present study, with no sample size restrictions and inclusion based only on recruitment time. Due to the rarity of E-cadherin deficiency (~8% of GC), this was the largest sample size available to the research team. Clinical databases were prospectively extracted and retrospectively analyzed. Inclusion criteria comprised histologically confirmed primary gastric adenocarcinoma, no chemotherapy or radiotherapy before surgery, radical gastrectomy, no history of gastrectomy or other malignant tumors, and complete clinical and pathological data. Patient's refusing to participate were excluded. The acquisition and utilization of tissue specimens were approved by the Ethics Committee of Ningbo No. 2 Hospital (approval nos. PJ-NBEY-KY-2019-153-01 and PJ-NBEY-KY-2012-681-08), and patients provided written informed consent.
Immunohistochemical staining and evaluation
Rabbit anti-human E-cadherin antibody (clone number, EP6; Beijing Zhongshan Jinqiao Biotechnology Co., Ltd.) was utilized for immunohistochemical staining. The initial specimens were fixed in 40 g/l formaldehyde for 7 h at 65°C and embedded in paraffin. Specimens from the paraffin embedded block were cut into 4-µm sections. The first section was routinely stained with hematoxylin-eosin for histological diagnosis and subsequent sections were stained for immunohistochemical analysis. E-cadherin immunohistochemical staining was performed using ABC detection system (Vector Laboratories, Inc.). The sections were incubated with a primary antibody against E-Cadherin (clone number, EP6; diluted at 1:200; cat. no. ZA-0565; Beijing Zhongshan Jinqiao Biotechnology Co., Ltd.) for 1.5 h at room temperature. Sections were dewaxed, and rehydrated. Antigen retrieval was performed in 0.1 mM citric buffer with a microwave at 700 W for 5 min. Endogenous peroxidase activity and non-specific bindings were blocked using a 30-min incubation with 3% hydrogen peroxide/methanol followed by a 30-min incubation with 5% goat serum, respectively. The sections were covered with HRP-conjugated secondary antibody at room temperature for 30 min. Thereafter, specimens were stained with 3′,3-diaminobenzidine tetrahydrochloride. The slides were then counterstained with hematoxylin, dehydrated, and evaluated by light microscopy. The results were interpreted via double-blind reading by three pathologists. Any tan-colored staining, indicative of a notable increase in cell membrane expression, was considered a positive signal (Fig. 1A), regardless of nuclear or cytoplasmic staining. E-cadherin-negative was defined as complete loss of membranous expression (Fig. 1B) (11,12).
Follow-up
Patients underwent follow-up every 3–6 months for the first 2 years postoperatively and annually thereafter until mortality or ≥5 years after radical surgery. Adjuvant chemotherapy based on 5-fluorouracil or platinum was recommended for all postoperative patients with stage II–III GC (American Joint Committee on Cancer/International Union against Cancer Tumor-Node-Metastasis classification system, 8th Edition) (13). Follow-up assessments included physical examinations, laboratory tests (complete blood count, liver function tests, tumor markers) and imaging tests [chest X-ray, B-scan ultrasound, gastroscopy, computed tomography (CT), magnetic resonance imaging or positron emission tomography-CT] to detect recurrence or metastasis. Disease-free survival (DFS) was defined as the time from surgery to locoregional recurrence, distant recurrence or mortality, while overall survival (OS) was defined as the time from the start of randomization to mortality from any cause. The median follow-up for the entire cohort was 52 months (range, 1–122 months), with follow-up of all patients included in the present study closing in October 2023.
Statistical analysis
Demographic characteristics of the E-cadherin-negative group (E-cadherin deficiency) and the E-cadherin-positive group were compared and analyzed. Continuous variables were compared using independent-samples t-test or Wilcoxon's rank-sum test, while categorical variables were compared using Pearson's χ2 test or Fisher's exact test as appropriate. Logistic regression analysis was employed to evaluate the univariate and multivariate associations between clinicopathological factors and E-cadherin deficiency. Odds ratios (ORs) and 95% confidence intervals were calculated. To mitigate selection bias, 1:4 propensity score matching analysis was performed for the E-cadherin-negative and E-cadherin-positive groups. Kaplan-Meier curves were utilized to estimate DFS and OS, with the log-rank test determining significance. Propensity scores were generated using a logistic regression model incorporating covariates such as age, sex, tumor location, tumor size, perineural invasion, lymphovascular invasion, pathological tumor (pT) category, pathological lymph node (pN) category, number of lymph node dissections, carcinoembryonic antigen (CEA) and adjuvant chemotherapy. Individuals in the E-cadherin-negative group were matched to those in the E-cadherin-positive group based on these propensity scores. All statistical tests were two-tailed, with P<0.05 considered to indicate a statistically significant difference. Statistical analysis was performed using SPSS software (version 25.0; IBM Corp.).
Results
Patient recruitment
Between January 2013 and December 2022, a total of 2,297 gastrectomies were performed at Ningbo No. 2 Hospital. Following application of the inclusion criteria, 723 patients were excluded, resulting in the analysis of 1,574 patients (104 in the E-cadherin-negative group and 1,470 in the E-cadherin-positive group). E-cadherin negativity was observed in 6.6% of cases (Fig. 2).
Clinicopathological factors and E-cadherin
E-cadherin deficiency was potentially associated with a family history of GC, tumor size, histological type, perineural invasion, pT category and pN category in GC (all P<0.05; Table I). Univariate logistic regression indicated potential associations between E-cadherin deficiency and a family history of GC, histological type, perineural invasion, pT category, pN category and CEA levels in GC (all P<0.05; Table II). Further multivariate logistic regression identified a family history of GC (OR, 7.60; P<0.001), poorly differentiated histology (OR, 8.67; P<0.001), perineural invasion (OR, 1.63; P=0.030) and elevated CEA levels (OR, 1.83; P=0.034) as independent risk factors for E-cadherin deficiency in all enrolled patients (Table III).
 | Table I.Baseline clinicopathological characteristics of the enrolled patients with or without E-cadherin expression. |
| Table II.Univariate regression analysis of clinicopathological factors associated with E-cadherin deficiency. |
| Table III.Multivariate regression analysis of clinicopathological factors associated with E-cadherin deficiency. |
Propensity score matching analysis
In a 1:4 match analysis, age, sex, tumor location, tumor size, perineural invasion, lymphovascular invasion, pT category, pN category, number of lymph node dissections, CEA levels and adjuvant chemotherapy were matched. After matching, 86 patients in the E-cadherin deficiency group and 344 patients in the E-cadherin-positive expression group were analyzed. No significant differences were observed in the covariates of age, sex, tumor location, tumor size, perineural invasion, lymphovascular invasion, pT category, pN category, number of lymph node dissections, CEA levels and adjuvant chemotherapy (all P>0.05; Table IV). Kaplan-Meier analysis revealed no statistically significant differences in 5-year DFS rates between the E-cadherin deficiency group and the E-cadherin-positive expression group (P=0.590; Fig. 3). Similarly, no significant differences were observed in 5-year OS rates between the two groups (P=0.863; Fig. 4).
| Table IV.Baseline characteristics of patients with or without E-cadherin expression after 1:4 propensity score matching. |
Discussion
GC histology samples from the Human Protein Atlas demonstrated that E-cadherin deficiency accounted for 8% of GC cases (14). The present study, encompassing 1,574 patients with resectable GC, revealed a proportion of E-cadherin deficiency at 6.6%, which is consistent with the results of the literature. However, another study from China reported that E-cadherin deficiency accounted for 34.5% of patients with GC (15). This result potentially differs from the present study due to inclusion of a limited sample size of 84 patients who had already undergone GC surgery. E-cadherin deficiency is a molecular marker event of GC, and its clinical value is reflected in genetic counseling (CDH1 mutation detection), pathological classification, prognostic stratification and individualized treatment decisions.
The prognosis of resectable GC may be associated with factors such as age, sex, tumor size, depth of invasion, lymph node metastasis and histological type (16). Older age (≥70 years) is an independent risk factor for postoperative complications (17); as some older patients do not receive systemic therapy, they may not experience a survival benefit from adjuvant chemotherapy or radiation therapy (18). However, Hoffman et al (19) reported that postoperative radiotherapy and chemotherapy did not markedly improve survival in older patients with gastric adenocarcinoma resection. It has also been suggested that younger patients have a higher mortality rate compared with older patients, as GC in younger patients exhibits more aggressive features and may be more advanced (20). In summary, the difference in prognosis of GC with age is controversial. A study by Suh et al (21) demonstrated no notable difference between male and female patient outcomes after resection for early-stage GC in younger patients. However, older men have worse OS rate compared with older women, as they generally have more comorbidities compared with women of the same age (22,23). Currently, there are no previous studies that suggest that sex is an independent factor in the prognosis of GC.
Del Rio et al (24) showed that, in patients with GC, tumor size is associated with the degree of malignancy of the tumor and it is a notable predictor of survival. There is a positive association between tumor size and lymph node metastasis, with larger tumors likely to lead to a worse prognosis by promoting lymph node metastasis. A study by Lee et al (25) found that undifferentiated GC was associated with lymph node metastasis, which may also be associated with GC prognosis. T, N and metastasis (M) stages are recognized as the most important independent prognostic factors for GC (26,27). TNM staging for GC remains the most important basis for the selection of clinical treatment strategies and the judgment of clinical prognosis (28).
The expression of E-cadherin has an effect on the prognosis of malignant tumors (1). E-cadherin downregulation leads to E-cadherin-mediated signaling pathway dysfunction, thereby changing cell polarity, increasing cell viability and promoting the EMT process, as well as cell invasion and migration (29). Inactivation of E-cadherin contributes to EMT and tumor progression through a number of signaling pathways, including Wnt signaling, Rho GTPases and epidermal growth factor receptor (EGFR) (30). E-cadherin also has a growth-inhibiting function, inhibiting cell-cell contact and inducing cell cycle arrest by upregulating cyclin-dependent kinase inhibitor 1B (31). E-cadherin deficiency leads to the loss of this growth-inhibiting function, and tumors are more likely to invade and metastasize (3). Chronic inflammation caused by bacterial infection erodes the gastric mucosa, resulting in its eventual regeneration by bone marrow-derived cells, leading to GC through metaplasia-dysplasia sequences. However, this phenomenon may be limited to cancer types that arise after extensive destruction of inflammatory tissue, such as stomach ulcers. It has been established that Helicobacter pylori infection leads to NF-κB activation in the gastric epithelium. NF-κB regulates the phenotype of epithelial cells during inflammation and contributes to inflammation-associated carcinogenesis (32). E-cadherin has the ability to downregulate NF-κB activity, thereby reducing NF-κB-mediated carcinogenic effects (32,33). Thus, E-cadherin deficiency leads to NF-κB activation (4). E-cadherin acts as a tumor suppressor, and downregulation of E-cadherin has been observed in various cancer types, such as breast cancer and cutaneous melanoma (34). Somatic mutations of the the E-cadherin gene CDH1 have been found in sporadic diffuse GC (35). Gene mutations are a major mechanism of silencing tumor suppressor genes. In addition to the downregulation of E-cadherin induced by CDH1 gene mutations, epigenetic factors can also regulate the expression of E-cadherin. DNA methylation is a major type of epigenetic alteration, and promoter hypermethylation often serves as a secondary mechanism for silencing genes (36). This may also be associated with the prognosis of GC.
The present study demonstrated that E-cadherin deficiency in patients with resectable GC is associated with a family history of GC, poorly differentiated tumors, perineural invasion and elevated CEA levels. Germline mutations in CDH1 are closely associated with HDGC, leading to a higher incidence of E-cadherin deficiency in patients with a family history of GC (37). Apart from CDH1 gene mutations, factors such as loss of heterozygosity at E-cadherin chromosomal loci, CDH1 promoter hypermethylation, transcriptional repression and post-translational modifications (such as abnormal glycosylation) contribute to E-cadherin deficiency (38). For example, the study by Tedaldi et al (39) utilized next-generation sequencing (NGS) analysis to demonstrate different methylation patterns in the regulatory region of the CDH1 enhancer, serving a crucial role in gene expression regulation and subsequent E-cadherin deficiency. NGS analysis holds promise for diagnosing family members of patients with familial GC, enabling them to undergo preventive total gastrectomy (39,40).
A study by Chen et al (15) indicated a notable association between E-cadherin expression and GC differentiation. E-cadherin expression is more frequently lost in signet ring cell and mucinous adenocarcinomas, while it is often maintained in GC with glandular or nodular formation. Previous studies have identified E-cadherin gene mutations in signet ring cancer, disrupting the Adhesome and facilitating interactions between human EGFR2 and mucin 4, leading to the formation of signet ring cell carcinoma (41,42). The present study further demonstrates the association between poorly differentiated tumors and the prognosis of GC. Studies across different cancer types, including breast, endometrial and prostate cancer, have demonstrated that the reduction or loss of E-cadherin expression is associated with poor differentiation (43–45). This may be attributed to E-cadherin deficiency contributing to tumor dedifferentiation, thereby enhancing invasiveness. Key regulatory transcription factors of EMT, such as Snail, Slug, transcription factor 3 and Smad interacting protein 1/zinc finger E-box binding homeobox 2, are actively involved in inhibiting junction proteins and desmosomes, which are responsible for epithelial cell differentiation (46,47). Previous studies have not extensively explored the associations between E-cadherin deficiency and perineural invasion in GC. We hypothesize that E-cadherin deficiency may enhance the invasiveness of GC, facilitating perineural invasion. Notably, prior studies have not established a direct association between CEA and E-cadherin deficiency. CEA tends to enhance tumor aggressiveness (48), and concurrently, the aggressiveness of E-cadherin deficiency is higher. Therefore, based on the present findings, it is plausible that the two factors may exhibit a synergistic effect. In conclusion, the present study is the first to report the association of CEA elevation with E-cadherin deficiency in GC.
A meta-analysis of 26 studies demonstrated a notable association between decreased E-cadherin expression and poor prognosis in patients with GC (49). E-cadherin serves a multifaceted role in cancer biology, not only influencing invasion and metastasis but also functioning as a tumor suppressor in various cancer types, including GC (50,51). However, the present results indicated no significant association between E-cadherin deficiency and the prognosis of resectable GC. This disparity may stem from differences in study focus, with the present study investigation centering on E-cadherin deficiency rather than decreased expression levels. Additionally, the heterogeneity in thresholds for decreased E-cadherin expression across the original studies in the meta-analysis, ranging from 5 to 90%, coupled with predominantly univariate analyses, contributes to heterogeneity. Consequently, while the meta-analysis suggested a worse prognosis in patients with GC with reduced E-cadherin expression, the confidence in these findings remains tentative. Thus, the association between E-cadherin expression and prognosis in patients with GC remains controversial.
The present study highlights the contentious nature of the associations between four factors associated with E-cadherin deficiency and the prognosis of GC, namely family history of GC, poorly differentiated tumors, perineural invasion and elevated CEA levels. While hereditary cases associated with known cancer susceptibility syndromes or genetic causes account for a small proportion of all GC cases (52), their prognostic implications compared with sporadic GC remain unproven due to limited case numbers. The prognostic importance of histological type in GC has been debated, with numerous studies suggesting it lacks independent prognostic value (26,53). Although perineural invasion is a critical pathway for cancer metastasis, its status as an independent prognostic factor for GC remains unclear (54). Similarly, the association between GC prognosis and elevated CEA levels is disputed. While CEA serves as a vital tumor marker, elevated serum levels may also occur in benign conditions. Numerous patients with advanced metastatic GC may not exhibit elevated CEA levels (55,56). In conclusion, the present study found no significant association between E-cadherin deficiency and the prognosis of resectable GC. If there are more studies on E-cadherin deficiency in the future, a relevant meta-analysis will be performed.
While the present study provides valuable insights into E-cadherin deficiency in patients with GC in China, it has several limitations. Firstly, the low prevalence of E-cadherin deficiency in clinical practice limits the sample size. Additionally, the study lacks sufficient follow-up time. There are five internationally recognized patterns of GC recurrence: Local recurrence, lymph node metastases, peritoneal metastases, hematogenous metastases and mixed recurrence (57). The present study classified the prognosis and a total of 163 out of 430 patients had relapsed. According to the five recognized patterns of GC recurrence, 5 of the cases were local recurrence, 18 were lymph node metastases, 128 were peritoneal metastases, 87 were hematogenous metastases and the remaining patients were mixed recurrences. The primary outcome of the present study was DFS. Due to the sample size, it was not possible to further classify specific recurrence patterns for statistical analysis. Moreover, the cases included were all of patients with resectable GC in stages I–III. After propensity matching, there were 86 patients with E-cadherin deficiency in the study. Among them, there were 14 patients with stage I disease, and none of them relapsed. There were 18 patients with stage II, of whom 6 had recurrence, and there were 54 in stage III, of whom 26 were recurrent. Due to sample size limitations, further stratification analysis could not be performed (especially in patients with stage I). If more samples become available in the future the results should be updated. Finally, E-cadherin deficiency was defined solely based on immunohistochemistry, overlooking other mechanisms such as CDH1 gene mutations, promoter hypermethylation, transcriptional repression and post-translational modifications. Although NGS analysis is recommended for comprehensive gene analysis associated with E-cadherin deficiency, financial and technical constraints precluded further analysis in the present study.
In conclusion, the present study demonstrated that the proportion of E-cadherin deficiency in resectable GC in China may be ~6.6% based on data from one hospital. E-cadherin deficiency was associated with a family history of GC, poorly differentiated tumors, perineural invasion and elevated CEA levels. However, the present study did not confirm a significant association between E-cadherin deficiency and the prognosis of GC.
Acknowledgements
Not applicable.
Funding
The present study was funded by the Zhu Xiu Shan Talent Project of Ningbo No. 2 Hospital (grant no. 2023HMYQ09), the Ningbo Clinical Research Center for Digestive System Tumors (grant no. 2019A21003) and Ningbo Medical Key Discipline (grant no. 2022-B09).
Availability of data and materials
The data generated in the present study may be requested from the corresponding author.
Authors' contributions
CZ and MD conceptualized the study and designed the experimental methods. DW, XL and ZX collected and analyzed the data. AX and PC performed the follow-up of the patients. FW and YY analyzed data. SJ and LG were responsible for interpretation of the data. CZ was responsible for writing the original draft and editing the figures. MD and DW reviewed and edited the manuscript. LG supervised the study and contributed to the revision of the manuscript. CZ, MD, DW, XL, ZX, AX, PC, FW, YY, SJ and LG confirm the authenticity of all the raw data. All authors read and approved the final manuscript.
Ethics approval and consent to participate
In accordance with the Declaration of Helsinki, the studies involving humans were approved by the Ethics Committee of Ningbo No. 2 Hospital (approval nos. PJ-NBEY-KY-2019-153-01 and PJ-NBEY-KY-2012-681-08). The participants provided their written informed consent to participate in the study.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
|
EMT |
epithelial-mesenchymal transition |
|
GC |
gastric cancer |
|
CEA |
carcinoembryonic antigen |
|
HDGC |
hereditary diffuse gastric cancer |
|
CT |
computed tomography |
|
DFS |
disease-free survival |
|
OS |
overall survival |
|
OR |
odds ratio |
|
CI |
confidence interval |
|
NGS |
next-generation sequencing |
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