Proteomic characterization of SMARCA-deficient esophageal adenocarcinoma reveals complement evasion and DNA repair-associated prognostic subgroups

BACKGROUND: Oesophageal adenocarcinoma (EAC) is an aggressive malignancy in which the SWI/SNF catalytic subunits SMARCA2 and SMARCA4 are frequently lost, yet the biological and clinical impact of these deficiencies remains unclear. METHODS: We analysed 113 EAC specimens using mass spectrometry-based proteomics, including 89 SMARCA-deficient and 24 SMARCA-proficient tumours. Additional immunohistochemical studies were conducted on 98 cases. Differential expression, pathway enrichment, and survival analyses were used to characterise proteomic alterations and identify prognostic features. RESULTS: SMARCA-deficient tumours showed frequent expression of complement-inactivating proteins CD55 and CD59 with distinctive apical and membranous localisation. SMARCA4-deficient patients had significantly poorer survival than both SMARCA2-deficient and SMARCA-proficient patients. Among neoadjuvantly treated SMARCA-deficient tumours, coordinated upregulation of DNA repair proteins separated patients into two prognostic subgroups. The DNA repair-low subgroup had markedly worse survival than both the DNA repair-high subgroup and SMARCA-proficient controls, whereas the DNA repair-high subgroup showed a trend toward improved outcomes. This DNA repair-associated pattern was not observed in neoadjuvantly treated SMARCA-proficient tumours. CONCLUSIONS: SMARCA-deficient EAC comprises biologically distinct subgroups with prognostic proteomic signatures. CD55 and CD59 expression may contribute to resistance to antibody-based immunotherapies by complement evasion, while DNA repair profiles could guide post-surgical treatment in neoadjuvantly treated patients.