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Clinicopathological characterization of Switch/Sucrose-non-fermentable (Swi/Snf) complex (ARID1A, SMARCA2,
Chao Cao1,2, Zi-Yun Wu3, Wei Liao1,4
1State 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.
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.
Insights
Switch/Sucrose-non-fermentable (Swi/Snf) complex deficiency is rare in endocervical adenocarcinoma but linked to aggressive disease and immune activation. Evaluating Swi/Snf status may guide new therapies for patients.
Area of Science:
- Oncology
- Molecular Biology
- Gynecologic Pathology
Background:
- Switch/Sucrose-non-fermentable (Swi/Snf) complex subunits are implicated in gynecologic cancers.
- The role of Swi/Snf subunits in endocervical adenocarcinoma (ECA) remains unclear.
- This study investigates Swi/Snf expression and its clinical impact in ECA.
Purpose of the Study:
- To evaluate Swi/Snf complex subunit expression in 604 ECA cases.
- To characterize clinicopathological and immune microenvironment features of Swi/Snf-deficient ECA.
- To determine the prognostic significance of Swi/Snf deficiency in ECA.
Main Methods:
- Utilized tissue microarrays for immunohistochemical staining of Swi/Snf subunits, MMR proteins, immune markers, and checkpoint ligands.
- Collected and reviewed clinicopathologic and histological data for 604 ECA cases.
- Performed statistical analysis to correlate Swi/Snf status with clinicopathological features, immune microenvironment, and patient survival.
Main Results:
- Overall Swi/Snf deficiency rate was 5.96%, with ARID1A, SMARCA2, and SMARCA4 being the most frequently deficient subunits.
- Swi/Snf-deficient ECA showed advanced FIGO stage, larger tumor size, deeper invasion, higher lymph node metastasis, poor differentiation, medullary features, high nuclear grade, necrosis, and increased stromal tumor-infiltrating lymphocytes (sTILs).
- Deficiency was associated with elevated immune cell densities, higher PD-L1 CPS, mismatch repair deficiency (MMRD), and shorter overall and disease-free survival.
Conclusions:
- Swi/Snf complex deficiency, though rare, is significantly associated with aggressive pathological features, an immunologically activated phenotype, and MMRD in ECA.
- Swi/Snf status evaluation may offer insights for novel therapeutic strategies in ECA.
- Further research into the functional consequences of Swi/Snf deficiency in ECA is warranted.
