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Clinicopathological characterization of Switch/Sucrose-non-fermentable (Swi/Snf) complex (ARID1A, SMARCA2, SMARCA4)-deficient endocervical adenocarcinoma

Cancer Cell International volume 25, Article number: 170 (2025) Cite this article

Abstract

Background

Subunits of the Switch/Sucrose-non-fermentable (Swi/Snf) complex, such as ARID1A, SMARCA4, SMARCA2, etc., have been implicated in the development of gynecologic cancers. However, their prevalence and clinical implications in endocervical adenocarcinoma (ECA) remain unclear. This study aimed to evaluate the expression of Swi/Snf complex subunits in ECA and characterize the clinicopathological and immune microenvironment features of Swi/Snf-deficient ECA.

Methods

We evaluated 604 ECA using representative tissue microarrays, collected clinicopathologic data, reviewed histological features, and performed immunohistochemical staining for several Swi/Snf complex subunits, mismatch repair (MMR), immune cell markers, and immune checkpoint ligands proteins.

Results

Among the 604 cases examined, five Swi/Snf subunit expression patterns were identified, including intact expression, deficient expression, ‘checkerboard’ expression, reduced expression, and heterogeneous expression. Deficiencies of ARID1A (3.97%, 24/604), SMARCA2 (2.32%,14/604), and SMARCA4 (1.49%, 9/604) were observed. Defining Swi/Snf deficiency as loss of any subunit, the overall deficiency rate was 5.96% (36/604). Swi/Snf-deficient ECA tended to advanced FIGO stage (III-IV, P = 0.041), larger tumor size (P < 0.001), deeper stromal invasion (≥ 1/3, P = 0.046), and higher lymph node metastasis rate (P = 0.037). Morphologically, Swi/Snf-deficient ECA displayed frequent poor differentiation (P = 0.001), medullary features (P < 0.001), high nuclear grade (P < 0.001), necrosis (P = 0.001), stromal tumor-infiltrating lymphocytes (sTILs, P < 0.001), peritumoral lymphocyte aggregation (P = 0.001), and tertiary lymphoid structures (TLS, P < 0.001). Immune subset analysis revealed significantly elevated densities of CD3⁺ T cells, CD8⁺ T cells, CD38⁺ plasma cells, CD56⁺ NK cells, CD68⁺ macrophages, and PD-1⁺ T cells in Swi/Snf-deficient ECA (P < 0.05). Swi/Snf-deficient ECA demonstrated higher PD-L1 combined positive score (CPS) positivity (P < 0.001), and was more frequently associated with mismatch repair deficiency (MMRD, P < 0.001). Survival analysis indicated shorter overall survival (median: 53 vs. 64.5 months, P = 0.0307) and disease-free survival (median: 52 vs. 60.5 months, P = 0.0228) in Swi/Snf-deficient ECA patients.

Conclusions

Swi/Snf complex deficiency is rare but significantly associated with NHPVA, aggressive pathological features, immunologically activated phenotypes, and MMRD. Swi/Snf status evaluation may inform novel therapeutic strategies for ECA patients.

Introduction

Endocervical adenocarcinoma (ECA) is characterized by a worsening prognosis and increasing annual incidence [1, 2]. ECA encompasses a diverse group of malignancies, classified by the 2020 WHO and IECC systems into HPV-associated adenocarcinoma (HPVA) and non-HPV-associated adenocarcinoma (NHPVA) subtypes. HPVA includes usual-type and mucinous variants, while NHPVA comprises gastric-type, clear cell, and other rare subtypes [3]. The classification relies on histology (mitotic/apoptotic activity), p16 expression, and HPV testing. Studies indicate that patients with NHPVA generally have worse survival outcomes compared to those with HPVA, leading ECA patients with limited options [4]. There is an urgent need for specific therapeutic targets and personalized treatment approaches to improve survival outcomes.

The Switch/Sucrose-non-fermentable (Swi/Snf) complex is a highly conserved ATP-dependent chromatin remodeling complex that utilizes ATP hydrolysis to drive nucleosome movement and regulate chromosome structure. The Swi/Snf complex consists primarily of three types: the cBAF complex (canonical BAF), the pBAF complex (polybromo-associated BAF), and the ncBAF (non-canonical BAF). These complexes comprise various subunits (such as ARID1A, SMARCA2, SMARCA4, and SMARCB1), and mutations in these subunits mediate tumorigenesis [5, 6]. Technological advancements like human cancer exome and whole-genome sequencing have revealed mutations or inactivation in Swi/Snf complex subunit genes across various tumors. Over 20% of cancers are associated with these mutations [6].

Research has explored the role of Swi/Snf complex subunits in specific tumors. In female reproductive system tumors, some subunit mutation patterns have been preliminarily identified, such as frequent ARID1A mutations in ovarian and endometrial clear cell carcinomas, and endometrioid adenocarcinomas [7, 8]. Furthermore, Swi/Snf-deficient tumors often exhibit multiple pathological features. For instance, ARID1A-deficient esophageal adenocarcinomas frequently show myeloid or mucinous differentiation [9], and ARID1A, SMARCB1, or SMARCA2-deficient gastrointestinal cancers typically present with solid nests, anaplastic cells, and rhabdoid morphology [10, 11]. It is worth mentioning that ARID1A deficiency impairs the DNA repair mechanism (e.g., MMR deficiency), resulting in elevated tumor mutational burden (TMB) and neoantigen-driven T-cell responses. High TMB enhances tumor immunogenicity by improving immune system recognition. Swi/Snf subunits modulate chemokines (CXCL9/10) and MHC-I expression, facilitating T cell and NK cell infiltration [12, 13]. In ARID1A-deficient ovarian cancer, PD-L1 positivity rates reach up to 47.1%, while ARID1A loss activates the NF-κB pathway to induce regulatory T cell (Treg) expansion and suppress antitumor immunity [14, 15, 16]. Notably, SMARCA4-deficient thoracic tumor patients with PD-L1 positivity treated with PD-1/PD-L1 inhibitor achieved a response rate of 42% [17]. Given ECA’s heterogeneity and lack of targeted therapies, investigating Swi/Snf deficiency may reveal prognostic biomarkers or immunotherapeutic opportunities. However, their role in ECA remains limited. Studies have shown that Swi/Snf-deficient tumors exhibit distinct clinicopathological features and may harbor potential therapeutic targets or immunotherapeutic approaches [6]. Therefore, investigating the clinical and pathological significance of Swi/Snf-deficient ECA is essential to advance our understanding and improve treatment strategies for this disease.

Method and materials

Patients and samples

604 ECA specimens along with complete clinical and pathological data were obtained from ECA patients who underwent surgical resection at Sun Yat-sen University Cancer Cente between January 2010 and July 2021. Excluded cases comprised in situ carcinoma, squamous cell carcinoma, adenosquamous carcinoma, tumors with neuroendocrine components, carcinosarcoma, and tumors suggestive of origin from the lower uterine segment, endometrium, or bilateral adnexa. These cases had not received neoadjuvant therapy and had tissue specimens adequately formalin-fixed and paraffin-embedded (FFPE) for immunohistochemical analysis. Follow-up information, also formerly collected, included the presence of, time to, and site of recurrence, along with time to last follow-up. Tumor recurrence criteria were determined according to NCCN/FIGO recommendations, by reviewing inpatient/outpatient records and evaluating clinical symptoms, imaging, and pathological findings. Ethics approval was obtained from the Institutional Review Board of Sun Yat-sen University Cancer Center.

Tissue microarray (TMA) construction and immunohistochemistry staining

The pathologist selected adequately fixed ECA specimens, prepared tissue blocks of appropriate size, and fixed them in 10% formalin solution for 24 hours. After rinsing with tap water, the tissue blocks underwent dehydration with sequential ethanol solutions of varying concentrations, each for 30 minutes, followed by three 1-hour treatments with absolute ethanol. The dehydrated tissue blocks were immersed in an xylene-absolute ethanol mixture for 1 hour and then transferred to pure xylene for clarification. Subsequently, the blocks were placed in a molten paraffin-xylene mixture for 1 hour and then transferred to molten pure paraffin for 3 hours. Finally, the tissue blocks were removed from the paraffin solution, placed in a section box with the cutting surface facing downward, and embedded with molten paraffin. According to the method described previously [18], we constructed the tissue microarray, containing 604 ECA and adjacent nontumorous tissues. We retrieved all histological sections for each case and selected representative adenocarcinoma foci and adjacent normal mucosa tissue blocks. Two tissue samples were precisely selected from the cancer nest area and one sample was from the normal cervical mucosa. These were used to construct TMA blocks with a tissue microarray spotter. For tumor morphological assessment, we retrieved complete H&E sections of tumor tissue archived in our hospital. IHC assessment was primarily based on TMA staining, conducted by a senior researcher to ensure reliability and reproducibility. Each case section was assessed under a multi-head microscope by two pathologists blinded to the SWI/SNF complex status, reaching a consensus. For cases showing SWI/SNF complex subunit and MMR protein defects on TMA, whole-cancer tissue sections were restained to rule out TMA staining artifacts. Using a tissue arraying instrument (MinicoreExcilon, Minicore, UK), each tissue core with a diameter of 4 µm was punched from the marked areas and re-embedded. Immunohistochemical staining was performed on thick sections of the TMA tissues. Deparaffinization, blocking, and incubation with primary antibodies against ARID1A, ARID1B, SMARCA2, SMARCA4, SMARCB1, SMARCC1, MSH2, MSH6, MLH1, PMS2, CD3, CD4, CD8, CD20, CD68, CD38, CD15, CD56, FOXP3, PD-1, PD-L1, p16, and Ki-67 were conducted, all antibody information was summarized in Table S1. Staining visualization utilized DAB (3,3’-diaminobenzidine), followed by counterstaining with Mayer’s hematoxylin. In immunohistochemical staining, tumors were considered deficient if there was a complete absence of nuclear staining in tumor cells for ARID1A, ARID1B, SMARCA2/BRM, SMARCA4/BRG-1, SMARCB1/INI-1, and SMARCC1. Conversely, any strong nuclear staining in tumor cells indicated intact status. (Fig. S1A) Cases with staining loss of Swi/Snf complex subunits on TMA were re-stained using tissue slides. MLH1, PMS2, MSH2, and MSH6 were deemed positive if nuclear staining was present in ≥ 1% of tumor cells, with non-tumor cell nuclear staining as control. A diffuse strong staining pattern in all p16 cores indicated p16-positive expression, while punctate, patchy staining, or no staining indicated p16-negative expression. According to the PD-L1 assessment criteria [19], expression is evaluated based on a combined positive score (CPS), with a threshold of ≥ 1 considered positive. Using an Olympus BX51 microscope (Scientific, Inc., New York, NY), the three high-power fields (HPF) with the highest number of IHC-stained immune cells in the tumor lesion are selected, and the number and density of immune cells are calculated (in cells/mm2). Staining procedures were overseen by a senior technical researcher, with staining results independently evaluated by two experienced pathologists.

Clinicopathologic review and morphological evaluation

The clinicopathologic data, including age and FIGO stage at diagnosis, depth of invasion, pattern of invasion, margin status, presence of lymph vascular invasion (LVI), and lymph node status, was previously collected. Strict criteria for assigning patterns A, B, or C to HPVA cases were performed using the WHO-endorsed criteria for pattern-based classification. Morphological evaluation utilized hematoxylin-eosin (H&E) stained slides, alltumor-containing slides were evaluated. The assessment focused on tumor features (classification, subtypes, Silva type, differentiation degree, nuclear grade, medullary and rhabdoid features, growth patterns, heterogeneity, and necrosis), and immune responses (stromal tumor-infiltrating lymphocytes, peritumoral lymphocytes, and tertiary lymphoid structures, etc.) The assessment of tumor heterogeneity was carried out under low magnification, observing the presence of two or more distinctly different growth patterns in the complete tumor tissue H&E sections.We selected the three high-power fields with the highest number of immune cells in the cancer nest (IHC staining) and calculated the number and density of immune cells (cells/mm²). Detailed assessment criteria are provided in Table S2 [3, 9, 20, 21, 22]. Two pathologists reviewed each case’s slides blinded to the Swi/Snf complex under a multi-headed microscope to reach a diagnostic consensus.

Statistical analysis

SPSS (version 25.0., IBM Corp) and MedCalc (version 20, MedCalc Software Ltd) were used to perform statistical analysis. Cases were divided into low and high groups using the median age (47.5 years), tumor size (2.65 cm), and stromal tumor-infiltrating lymphocytes (sTILs, 15%). The Mann-Whitney test or the Kruskal-Wallis test determined differences in continuous variables between groups. Fisher’s exact test or Chi-Square test was used to analyze categorical variables between groups. Kaplan-Meier analysis, log-rank test, and univariate and multivariate COX regression analysis were used to evaluate survival prognosis. The threshold for statistical significance was P < 0.05.

Results

Swi/Snf complex deficiency is frequently observed in NHPVA

In this study, immunohistochemical staining was used to systematically detect six subunits of the Swi/Snf complex in 604 ECA samples (Fig. S1A). Based on staining patterns, the expression of these subunits was categorized into five types: intact expression, deficient expression, ‘checkerboard’ expression, reduced expression, and heterogeneous expression (Fig. 1A). The results showed significant deficiency of three subunits: ARID1A, SMARCA2 (BRM), and SMARCA4 (BRG1) (Fig. 1B). Defining Swi/Snf deficiency as loss of any subunit, 36 cases of Swi/Snf-deficient ECA were identified, with an overall defect rate of 5.96% (36/604). Specifically, the defect rates were 3.97% (24/604) for ARID1A, 2.32% (14/604) for SMARCA2 (BRM), and 1.49% (9/604) for SMARCA4 (BRG1) (Fig. 1C). Further analysis revealed that subunits of the Swi/Snf complex can be either singly or co-deficient. 13 cases were ARID1A-deficient only, 4 were SMARCA2-deficient only, and 8 were SMARCA4-deficient only. Specifically, 10 cases were both ARID1A-deficient and SMARCA2-deficient, one case was both ARID1A-deficient and SMARCA4-deficient, and no case were both SMARCA2-deficient and SMARCA4-deficient (Fig. 1D). Among these Swi/Snf-deficient cases, 29 were HPVA (22 usual subtype, 5 infiltrating stratified mucinous carcinoma, 2 mucinous adenocarcinoma), and 7 were NHPVA (6 gastric-type carcinomas, 1 clear cell carcinoma) (Fig. S1B). The deficiency rate of ARID1A/SMARCA2/SMARCA4A was significantly higher in the NHPVA group (15.2%) than in the HPVA group (5.2%) (P = 0.015) (Table 1; Fig. 1C). ARID1A and SMARCA2 deficiencies were more common in NHPVA, especially in the gastric type adenocarcinoma (P < 0.05) (Table S3). SMARCA4 deficiency occurred exclusively in the HPVA group, with a higher deficiency rate in infiltrating stratified mucinous carcinomas (P = 0.02) (Table S3).

Fig. 1
figure 1

Expression pattern of Swi/Snf-deficient ECA. (A) Representative images of Swi/Snf complex subunits staining patterns in ECA. (a) Diffuse nuclear staining of SMARCA2 (IHC, 20×); (b) Complete deficiency of SMARCA2 expression, with positive stromal cells as an internal control (IHC, 20×); (c) ‘checkerboard’ staining pattern (SMARCA2, IHC, 20×); (d) Reduced expression (ARID1B, IHC, 20×); (e-f) Tumor heterogeneity deficiency of SMARCA4 (HE, IHC, 20×, intact expression in the bottom area showing gland-forming carcinoma cells, deficiency expression in the top area showing solid growing tumor cells). (B) Protien-deficiency of ARID1A, SMARCA2, and SMARCA4 in ECA. First line: (a) ECA (HE, ×10) with deficiency of ARID1A expression (b) (IHC, 20×) in gastric type ECA. Second line: (c) ECA (HE, ×10) with deficiency of SMARCA2 expression (d) (IHC, 20×). Third line: (e) ECA (HE, ×10) with deficiency of SMARCA4 expression (f) (IHC, 20×). (C) Statistical picture of Swi/Snf-deficient ECA. (a) Frequencies of the deficiency of ARID1A, SMARCA2, and SMARCA4, (b) Swi/Snf-deficient ECA (ARID1A, SMARCA2, or SMARCA4) was significantly correlated with NHPVA (15.2% and 5.2%, ‘*’ represents P < 0.05). (D) The Venn diagram showed concurrent deficiency of ARID1A, SMARCA2, and SMARCA4

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Table 1 Baseline characteristics of Swi/Snf-deficient ECAs
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Clinicopathological characteristics of Swi/Snf-deficient ECA

ECA patients were categorized into Swi/Snf-deficient (any component of the Swi/Snf complex showing deficient expression in ECA) and Swi/Snf-intact (all components of the Swi/Snf complex showing intact expression in ECA) groups. The associations of Swi/Snf-deficient expression with clinical and pathological parameters are summarized in Table 1 and S3. Loss of ARID1A expression was significantly associations with age (P = 0.014), family history of cancer(P = 0.03), advanced FIGO stage (P = 0.033), larger tumor sizes (P < 0.001), negativity for p16 expression (P < 0.001), and dMMR (P < 0.001). Loss of SMARCA2 expression was statistically significant associations with larger tumor sizes (P = 0.02), negativity for p16 expression (P < 0.001), and dMMR (P < 0.001; Table S3). Similarly, loss of SMARCA4 expression had statistically significant associations with LVI (P = 0.021). There were no statistical differences in the other clinicopathological parameters. Compared to the Swi/Snf-intact group, Significant differences were found in the Swi/Snf-deficient group across several metrics: (1) disease progression risk was higher, with a greater proportion at FIGO III-IV stages (27.8% vs. 15.0%, P = 0.041); (2) tumor aggressiveness was indicated by larger maximum tumor size (median 3.5 cm vs. 2.5 cm, P < 0.001) and deeper stromal invasion (≥ 1/3 in 86.1% vs. 70.6%, P = 0.046); (3) metastatic potential was reflected in a higher lymph node metastasis rate (33.3% vs. 19.0%, P = 0.037). No significant differences were observed between groups regarding age, family history, lymphovascular invasion (LVI), or surgical margin status (P > 0.05) (Table 1). In the HPVA group, the proportion of Silva C type was significantly higher in the Swi/Snf-deficient group (93.1%, 27/29) compared to the Swi/Snf-intact group (67.0%, 354/529, P = 0.007), as indicated in Table 1; Fig. 2. Regarding tumor MMR status, the Swi/Snf-deficient group often presents with dMMR (22.2%, 8/36), a significantly higher occurrence rate compared to the Swi/Snf-intact group (0.7%, 4/568, P < 0.001) (Table 1, and Fig. 3A-B).

Fig. 2
figure 2

The microscopic representative pictures with significant differences in morphology in Swi/Snf-deficient ECA. (A-B) Swi/Snf-deficient ECA was poorly differentiated, exhibiting medullary features and marked nuclear pleomorphism, with some nuclei showing vacuolar changes (red arrows). (C-E) The stroma frequently demonstrated necrosis, lymphocytic infiltration (including stromal tumor-infiltrating lymphocytes (sTILs), peritumoral lymphocytic aggregation, and formation of tertiary lymphoid structures (TLS). (F-J) In contrast, Swi/Snf-intact ECA rarely exhibited these morphological features

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Fig. 3
figure 3

Swi/Snf-deficient ECA showed a significant correlation with dMMR and immune microenvironment. (A) Representative images under the microscope showed that deficiency of ARID1A, SMARCA2, and SMARCA4 combined with dMMR. (a-e) Deficiency of ARID1A, SMARCA2, MLH1, and PMS2 (N = 1, HE and IHC, 20×); (f-j) deficiency of ARID1A, SMARCA2, MSH2, and MSH6 (N = 5, HE and IHC, 20×); (k-o) deficiency of ARID1A, SMARCA4, and MSH6, and the intact expression of MSH2 (n) as contrast (N = 1). (B) Swi/Snf- deficient ECA was significantly correlated with dMMR, including ARID1A-deficient, and SMARCA2-deficient respectively, except SMARCA4-deficient, which shows no statistical difference. (C) Representative H&E and IHC images under the microscope showed different expressions compared Swi/Snf-deficient with Swi/Snf-intact ECA. (D) The density of CD3, CD8, CD38, CD56, and CD68 in Swi/Snf-deficient ECA was higher, and the positive rate PD-L1 (CPS) was also significantly higher (The density of IHC-positive immunocytes underwent natural logarithmic conversion. ‘*’ means P < 0.05; ‘* *’ means P < 0.01; ‘* * *’ means P < 0.001; ns, no significance)

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Swi/Snf-deficient ECA exhibits distinct morphological features

The associations of Swi/Snf-deficient expression with morphological features were summarized in Table S4. Loss of ARID1A expression was statistically significant associations with medullary features (P < 0.001), tumor heterogeneity (P = 0.004), higher nuclear grade (P = 0.008), higher mitosis (P = 0.048), and necrosis (P = 0.003). Loss of SMARCA2 expression demonstrated statistically significant associations with medullary features (P < 0.001), poor differentiation (P = 0.014), and higher nuclear grade (P = 0.001). Loss of SMARCA4 expression exhibited statistically significant associations with medullary features (P = 0.001), tumor heterogeneity (P < 0.001), and poor differentiation (P = 0.007). Moreover, compared to the Swi/Snf-intact group, the Swi/Snf-deficient group showed significant associations with medullary features (P < 0.001), tumor necrosis (P = 0.001), poor differentiation (P < 0.05), tumor heterogeneity (P < 0.05), and higher nuclear grade (P < 0.05). There were no statistically significant connections found between Swi/Snf-deficient tumors and other morphological features such as signet ring cell carcinoma components and micropapillary growth (P > 0.05). These morphological characteristics are detailed in Table 1, and representative micrographs are depicted in Fig. 2.

Swi/Snf-deficient ECA exhibits an abundant immunological microenvironment

This study demonstrated that Swi/Snf-deficient ECA exhibited a distinct immunogenic tumor microenvironment characterized by heightened host inflammatory responses and immune activation. Morphological analysis revealed significant associations between Swi/Snf deficiency and increased stromal tumor-infiltrating lymphocytes (sTILs, P < 0.001), peritumoral lymphocyte aggregation (P = 0.001), and tertiary lymphoid structures (TLS, P < 0.001) (Table 2; Fig. 2). Immune marker profiling (Tables S5) showed that ARID1A-deficient ECA was strongly associated with elevated infiltration of CD3⁺ (P = 0.001), CD8⁺ (P < 0.001), CD38⁺ (P = 0.002), CD56⁺ (P = 0.026), and CD68⁺ (P < 0.001) immune cells, and broader analyses further linked SMARCA2-deficient tumors to increased CD15⁺ (P = 0.004) cell densities (Table S5). In contrast, SMARCA4-deficient ECA displayed reduced FOXP3⁺ regulatory T cells (P = 0.032), suggesting subtype-specific immune modulation. Quantitative comparisons (Table 3; Fig. 3C-D) confirmed significantly higher immune cell densities in Swi/Snf-deficient ECA, including CD3⁺ (437.50/mm² vs. 291.67/mm², P = 0.004), CD8⁺ (363.20/mm² vs. 166.67/mm², P < 0.001), CD38⁺ (241.67/mm² vs. 93.75/mm², P < 0.001), CD56⁺ (75% Percentile, 8.33/mm2 vs. 2.08/mm2, P = 0.009), CD68⁺ (73.82/mm² vs. 31.25/mm², P < 0.001), and PD-1⁺ cells (57.64/mm² vs. 16.67/mm², P = 0.003). Additionally, Swi/Snf-deficient ECA showed higher PD-L1 positivity (combined positive score, P < 0.05, Table 3; Fig. 3C-D), particularly in ARID1A- and SMARCA2-deficient subgroups (P < 0.05, Tables S5).

Table 2 Morphological characteristics of Swi/Snf-deficient ECAs
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Table 3 Expressions of immune markers of Swi/Snf-deficient ECAs
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Patients with Swi/Snf-deficient ECA exhibit poorer prognosis

We collected patient follow-up information to conduct survival analysis, with a median follow-up period of 64 months in this study. Kaplan-Meier analysis and log-rank tests revealed significantly worse overall survival (OS, median: 53 vs. 64.5 months, P = 0.0307) and disease-free survival (DFS, median: 52 vs. 60.5 months, P = 0.0228) prognoses in Swi/Snf-deficient patients compared to Swi/Snf-intact patients (P < 0.05). Subsequent stratified survival analysis indicated that ARID1A and SMARCA2 showed worse OS, but no statistical correlation was found, except for worse DFS in SMARCA4-deficient patients (P = 0.0223), as depicted in Fig. 4. Univariate and multivariate Cox regression analyses were performed on prognostic indicators, revealing that Swi/Snf-deficiency and tumor size significantly increased the risk of tumor progression in patients with ECA (HR = 18.451, 95% CI: 1.098-309.957, P = 0.043; HR = 2.196, 95% CI: 1.294–3.727, P = 0.004; HR = 4.243, 95% CI: 2.183–8.247, P < 0.001). Multivariate Cox analysis indicated that Swi/Snf-deficiency, tumor size, and lymph node metastasis (LNM) were independent prognostic factors for ECA, as detailed in Table 4. Among the 604 cases of ECA we collected, there were 95 patients in III-IV stage, of which 8 patients did not receive any treatment after surgery, 87 patients received any one of chemotherapy, radiotherapy, immunotherapy, and targeted therapy (such as bevacizumab) after surgery, and 124 patients were patients with recurrent ECA, of which 10 patients did not receive any treatment after surgery, 114 patients received any one of chemotherapy, radiotherapy, immunotherapy, and targeted therapy (such as bevacizumab) after surgery, and 24 patients received immunotherapy (including #Case 33 with ARID1A-deficient). We compared their median OS and found that #Case 33’s OS was 49 months, which was longer than that of patients with recurrent (41.5 months vs. 35 months) or III-IV stage (46 months vs. 35.5 months), who received or did not receive treatment after surgery. Additionally, high-throughput sequencing of tumor gene variation identified 4 individual cell variants in #Case 33. Clinically significant variants included ARID1A gene p.R1276 and KRAS gene p.A146T, with a tumor mutation burden (TMB) of 1.99 mutations per megabase (Mb), as illustrated in Table S6 and Fig. S2.

Fig. 4
figure 4

Swi/Snf-deficient ECA patients exhibited a worse survival prognosis. Kaplan-Meier analysis and log-rank tests revealed the following: (A) Patients with SwiSnf-deficient ECA had significantly shorter overall survival (OS), patients with ARID1A-deficient, SMARCA2-deficient, and SMARCA4-deficient showed a trend toward shorter OS, the differences were not statistically significant. (B) Patients with Swi/Snf-deficient ECA had shorter disease-free survival (DFS). The stratified analysis further indicated that only patients with SMARCA4-deficient ECA exhibited significantly shorter DFS

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Table 4 Univariate and multivariate Cox regression analysis of overall survival in 604 ECAs
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Discussion

Previous studies have indicated the presence of Swi/Snf complex subunit losses in endocervical cancer, while research specifically on ECA remains notably scarce. Our study assembled a substantial cohort of ECA cases for the first time, revealing the loss of ARID1A, SMARCA2, and/or SMARCA4 subunits. Our findings highlight distinct clinicopathological characteristics of Swi/Snf-deficient ECA.

Literature is limited on Swi/Snf subunit loss in ECA. Hanbyoul Cho et al. reported a 24% loss rate (6/25) of ARID1A in endocervical cancer [23]. Our study of 604 cases revealed an overall loss rate of Swi/Snf subunits at 5.96%. Patients with Swi/Snf-deficient ECA had worse overall survival and disease-free survival, with more adverse prognostic factors such as advanced FIGO stages, larger tumor diameters, Silva C type, and lymph node metastasis, particularly in gastric-type adenocarcinomas. This similarly aligns with literature reports [9, 23, 24]. As for morphology features, Drage MG et al., collected 120 cases of esophageal adenocarcinoma, finding that ARID1A-deficient tumors exhibited medullary and mucinous phenotypes [9]. Similarly, Tsuruta S’s research showed that solid-type gastric adenocarcinoma shows a frequent loss in ARID1A, SMARCA4, SMARCA2, and BAF155 [11]. Our study revealed that Swi/Snf-deficient ECA often displayed solid and medullary characteristics, consistent with existing literature. Notably, we did not observe SMARCB1 loss or rhabdoid morphology, possibly due to our stringent inclusion criteria and the nature of subunit loss. Furthermore, rhabdoid morphology is often reported in soft tissue tumors with SMARCB1 or SMARCA4 loss [25, 26].

Multiple pieces of research have proved that Swi/Snf subunit loss is closely related to dMMR and prominent lymphocyte infiltration [8, 27, 28, 29, 30]. Heinze K, et al., studied 1078 ovarian endometrioid adenocarcinoma and found that ARID1A loss was associated with dMMR (P < 0.001) and CD8 + TIL (P = 0.008) [28]. Zhang Z et al. collected 1248 postoperative patients with gastric adenocarcinoma and found that the negative expression of ARID1A occurred more frequently in microsatellite instability subtypes and caused increased CD4 and PD-L1 expression [29]. Shen J et al. found that ARID1A inactivation compromised MMR and increased mutagenesis in a proteomic screen. They also identified that the ARID1A-deficient ovarian cancer cell line in syngeneic mice displayed increased mutation load, elevated numbers of tumor-infiltrating lymphocytes, and PD-L1 expression [12]. In our study, ECA lacking Swi/Snf subunits showed increased immune cell infiltration and PD-L1 expression. This suggests a robust immune microenvironment, including CD3 and CD8 + T cells, plasma cells, NK cells, and macrophages. Loss of these subunits is also correlated with dMMR. This parallels findings in ARID1A and SMARCA2-deficient cases, indicating a consistent immune response. Some studies have identified the relationship between Swi/Snf-deficient tumor dMMR and abundant immune microenvironment. On the one hand, ARID1A interacts with MMR protein MSH2. ARID1A recruited MSH2 to chromatin during DNA replication and promoted MMR. Conversely, ARID1A inactivation compromised MMR and increased mutagenesis [12]. When mismatch repair protein is deficient, this can result in the creation of novel antigens recognized by cytotoxic T lymphocytes (CD8 + T cells), thereby intensifying the immune response and augmenting tumor lymphocyte infiltration [31, 32]. On the other hand, Swi/Snf-deficient can directly upregulate the number of T cells. Guo A et al., established mammalian canonical SMARCA4/SMARCA2-associated factor (cBAF) as a negative determinant of Memory T (Tmem) cell fate. Several components of the cBAF complex are essential for the differentiation of activated CD8 + T cells into T effector (Teff) cells, and their loss promotes Tmem cell formation in vivo [33]. Another study identified that CD8 + T cell exhaustion (Tex) limits disease control during chronic viral infections and cancer. Disruption of PBAF enhances Tex-cell proliferation and survival[34]. Consequently, it was practicable to explain the phenomenon that ARID1A/SMARCA2/SMARCA4 deficient ECA were related to dMMR and abundant immune microenvironment.

Swi/Snf-deficient ECA exhibited actionable biomarkers, including high PD-L1 expression, dMMR, and probably elevated tumor mutational burden (TMB), which predict responsiveness to PD-1/PD-L1 inhibitor [35]. Importantly, a multi-omics model integrating IHC-based ARID1A/SMARCA4 loss, MMR status, and TMB scoring may optimize patient stratification. Beyond immunotherapy, synthetic lethality strategies target specific Swi/Snf subunits: for instance, ARID1A-deficient tumors are vulnerable to ARID1B/PARP inhibitors (e.g., olaparib), whereas SMARCA4-deficient tumors may respond to SMARCA2 bromodomain inhibitors [36, 37, 38]. Furthermore, epigenetic-immune crosstalk further provides therapeutic opportunities, as EZH2 inhibitors (tazemetostat) can reverse PRC2-mediated immunosuppression to enhance PD-L1 and T-cell infiltration, while HDAC inhibitors combined with PD-1 blockade may improve antigen presentation through chromatin remodeling [39, 40, 41]. However, despite the utility of IHC for detecting Swi/Snf defects, limitations such as antibody variability and tumor heterogeneity necessitate complementary approaches (e.g., NGS, FISH). Mechanistically, Swi/Snf deficiency drives immunogenicity via genomic instability-induced neoantigenesis and chemokine/PD-L1 upregulation, yet paradoxically correlates with immune exhaustion [34 ]. Supporting this, basic research demonstrates that epigenetic modulation can restore CD8 + T-cell infiltration, thereby highlighting context-dependent vulnerabilities [37, 38]. Future priorities include validating clinical benefits through trials (e.g., NCT04591431, the ROME trial) [42], employing spatial multi-omics to map tumor-immune interactions, and developing liquid biopsies for real-time Swi/Snf defect monitoring. These integrated strategies aim to translate Swi/Snf biology into precision therapies for ECA..

This study has several limitations. Firstly, there are some limitations of TMA in assessing TILs, including: 1) spatial heterogeneity: small cores (1–2 mm) may underrepresent TIL distribution patterns (e.g., TLS at tumor-stroma interfaces) [43]; 2) quantification bias: selective sampling may overestimate sTILs, while single stains limit functional TIL subtyping; 3) lost spatial interactions: immune synapse or immunosuppressive niches cannot be resolved [44]. To address these limitations, we employed three tumor cores per case (sampling both center and periphery) with H&E-guided quality control, ensuring our approach maintains practical feasibility and analytical reliability. Secondly, we only detected six Swi/Snf subunits with high deficiency frequency and did not detect all the other subunits. Furthermore, it’s a single-center study, lacking multi-center validation. Additionally, while this study focused on ECA with Swi/Snf subunit deficiency, other histological types of endocervical cancer remain unexplored. Finally, genetic and molecular evidence is needed to support the findings of this study further.

Conclusions

Swi/Snf-deficient ECA shows an overall low deficiency rate (5.96%) but the higher prevalence in NHPVA. Swi/Snf-deficient ECA has distinct clinicopathological features, such as advanced FIGO stage, obvious medullary features, poor differentiation, dMMR, and abundant immune microenvironment. The identification of SWI/SNF-deficient ECA cases may improve therapeutic outcomes through targeted and immunotherapeutic interventions.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

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Funding

This work was supported by grants from The National Natural Science Foundation of China (No. 82072853).

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  1. Chao Cao, Zi-Yun Wu, Wei Liao contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China

    Chao Cao, Wei Liao, Li-Jun Wei, Hao-Yu Liang, Xia Yang, Rong-Zhen Luo & Li-Li Liu

  2. Department of Pathology, Sun Yat-sen University Cancer Center, 651# Dong Feng Road East, Guangzhou, Guangdong, 510060, P.R. China

    Chao Cao, Li-Jun Wei, Hao-Yu Liang, Xia Yang, Rong-Zhen Luo & Li-Li Liu

  3. Department of Urology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510080, P.R. China

    Zi-Yun Wu

  4. Department of Intensive Care Unit, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China

    Wei Liao

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Contributions

Conception and design: C Cao, R.-Z. Luo, L.-L. Liu. Development of methodology: C Cao, X. Yang. Acquisition of data (acquired and managed patients, provided facilities, etc.): C Cao, R.-Z. Luo, L.-L. Liu, L.-J. Wei. Analysis and interpretation of data (e.g., statistical analysis): C Cao, L.-L. Liu. Writing, review, and/or revision of the manuscript: C Cao, Z.-Y. Wu, W Liao, L.-L. Liu. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): H.-Y. Liang, L.-J. Wei. Study supervision: R.-Z. Luo, L.-L. Liu.

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Cao, C., Wu, ZY., Liao, W. et al. Clinicopathological characterization of Switch/Sucrose-non-fermentable (Swi/Snf) complex (ARID1A, SMARCA2, SMARCA4)-deficient endocervical adenocarcinoma. Cancer Cell Int 25, 170 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12935-025-03794-y

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Cancer Cell International

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