18例SMARCA4缺失或基因突变肺部肿瘤患者的临床病理与基因特征以及预后分析OA

Background and objective The diagnosis of SMARCA4-altered pulmonary tumors primarily relies on the detection of protein loss by immunohistochemistry(IHC).However,the concordance between IHC and genetic testing re-sults,as well as the clinical and biological differences caused by various mutation types,require further investigation.This study aimed to explore the clinicopathological,genomic characteristics,as well as the prognosis,of these tumors.Methods A total of 18 consecutive cases of pulmonary tumor patients with SMARCA4 deficiency/mutation confirmed by IHC or genetic testing were retrospectively enrolled for clinical,genomic,and prognostic analysis.Based on the variant type,patients were categorized into Class 1(protein loss or loss-of-function gene mutations,n=10)and Class 2(missense mutation or other variants of un-known significance without protein loss,n=8)for intergroup comparison.Results Seventeen cases were diagnosed with non-small cell lung cancer(NSCLC)and one was diagnosed with thoracic SMARCA4-deficient undifferentiated tumor(SD-UT).Genotype-phenotype correlation analysis revealed that truncating mutations consistently led to protein loss,whereas missense mutations mostly did not.Two cases with protein loss but negative genetic testing results were identified.Class 1 alterations showed trends towards higher tumor mutational burden(TMB)(median 9.3 vs 4.7 Muts/Mb)and lower programmed cell death ligand 1(PD-L1)expression(60.0%vs 25.0%with<1%expression)compared to Class 2,but the differences were not statistically significant(P>0.05).Two patients with co-occurring epidermal growth factor receptor(EGFR)L858R mutations showed poor initial response to third-generation EGFR-tyrosine kinase inhibitor monotherapy,but the efficacy was observed after combination with other therapies.Among stage IV patients,the median overall survival(OS)was 10.3 months for Class 1 and 19.9 months for Class 2(P=0.967).Fourteen patients(77.8%)received immune checkpoint inhibitors(ICIs)combined with chemotherapy.Among them,8 patients(57.1%)achieved an OS exceeding 12 months,and 7 patients(50.0%)exceeded 24 months.Conclusion SMARCA4 gene mutations are not entirely consistent with IHC protein loss,necessitating combined interpretation.When SMARCA4 alterations co-exist with EGFR mutations,targeted monotherapy efficacy may be limited,and combination strategies should be considered.Classifying SMARCA4 alterations into Class 1 and Class 2 may have prognostic implications and could help predict the tumor immune microenvironment status(TMB and PD-L1).ICIs combined with che-motherapy is currently one of the main treatment options for patients with advanced SMARCA4-altered pulmonary tumors and showed potential efficacy in this study.