Clinicopathological Features And Molecular Alterations Of SMARCA4-deficient Non-small Cell Lung Cancer

ObjectiveTo study the molecular alterations and prognosis in SMARCA4-deficient pulmonary adenocarcinoma and explore the expression of SMARCA4(BRG-1)in non-small cell lung cancer and its related clinical pathology characteristics.Methods(1)Next generation sequencing(NGS)technology was applied to analyze the mutation status of 110 pulmonary adenocarcinoma cases and divided them into SMARCA4 mutation and wild type groups,comparing their differences in clinical pathology characteristics,common driver genes and prognosis.(2)The immunohistochemistry method was used to evaluate the expression of SMARCA4(BRG-1)in 194 tissue microarray cases of non-small cell lung cancer and analyze the correlation between clinical pathology characteristics and SMARCA4(BRG-1)expression intensity.Meanwhile,16 cases with SMARCA4 expression deficiency were selected to observe histological and immunohistochemical characteristics.Results(1)A total of 143 cancer-related genes and 502 gene mutation types were detected by the next-generation sequencing in 110 cases pulmonary adenocarcinoma.The most common mutation types were TP53(63.6%),EGFR(53.6%),SMARCA4(17.3%),STK11(10.9%),PIK3CA(10.9%),KRAS(10.0%),NF1(7.3%).(2)19 cases with SMARCA4 mutation were confirmed.Compared with the wild type group,the SMARCA4 mutation type group was mainly male smoker and with rare EGFR mutation.As for prognosis,the SMARCA4 mutation type group showed shorter survival time.In addition,these mutations with SMARCA4 defective expression were mainly nonsense(75%)and frameshift(25%)mutations.(3)Among the 194 cases of tissue microarray,there were 4(2%)cases with SMARCA4(BRG-1)negative expression,18(9.3%)cases with weakly positive expression,130(67.0%)cases with moderately positive expression,and 42(21.6%)cases with strongly positive.Comparing SMARCA4(BRG-1)staining intensity with the clinical pathology characteristics,it was presented that SMARCA4(BRG-1)deficiency was statistically different in patients with smoking from positive cases,while no statistical significance in other indexes.(4)In SMARCA4(BRG-1)deficient pulmonary adenocarcinoma,there were two characteristic histological morphologies.One was that the tumor cells were composed of large cohesive epithelial cells arranged in compact solid nests and sheets with copious eosinophilic occasionally clear cytoplasm and vacuole nucleus.The other was characterized by rhabdoid cells with eosinophilic eccentric cytoplasm and arranged in solid nests or alveolar patterns.All cases were always accompanied by more or less necrosis,and in the background of most cases,we can find varying amounts of eosinophils infiltration.(5)On limited immunohistochemistry,we observed that there were 3/6(50%)cases with TTF-1 expression,3/5(60%)cases with CK7 expression,and 0/4(0%)case with Napsin A expression in adenocarcinoma and adenocarcinoma components of adenosquamous carcinoma.The squamous carcinoma and squamous carcinoma components of adenosquamous carcinoma both were P40 expression.In poorly differentiated neoplasm,CK was expressed in 3/4(75%)cases,TTF-1 was expressed in 1/4(25%)cases,Vimentin was expressed in 2/4(50%)case,P40 was expressed in 0/2(0%)case.In addition,CK expression accounted for 5/8(62.5%),VIMENTIN expression accounted for 3/6(50%),P53 expression accounted for 6/9(66.7%),and PDL-1 ≥1% positive expression were 4/9(44.4%)in all cases.Conclusion(1)SMARCA4-mutated pulmonary adenocarcinoma mainly occurs in male smokers with rare EGFR mutation.(2)Kaplan-Meier analysis showed that the overall survival of SMARCA4-mutated pulmonary adenocarcinoma is shorter than that of SMARCA4 wild type,and pulmonary adenocarcinoma with SMARCA4 mutation may indicate a poor prognosis.(3)The deficiency of BRG-1 was rare in NSCLC.Nonsense mutations and shift mutations in SMARCA4 genes may be common causes of BRG-1 deficiency.(4)In BRG-1 deficient non-small cell lung cancer,The morphological characteristics of large cells with abundant cytoplasm and rhabdoid cells phenotype have certain significance in BRG-1 deficient lung adenocarcinoma.In addition,TTF-1 rarely expressed in BRG-1 deficient lung adenocarcinoma,and some cases have positive expression of Vimentin,which is easy to cause misdiagnosis.