title: Loss of function of SWI/SNF chromatin remodeling genes leads to genome instability of human lung cancer.
abstract: SWI/SNF chromatin remodeling complexes are frequently mutated in a variety of human cancers. We investigated the mutation incidence and the role of mSWI/SNF (BAF) complexes in human lung cancer. In the present study, we analyzed somatic mutations of BAF complexes and other driver mutated genes of lung carcinoma deposited in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. BAF complexes were mutated in 282 of 803 (35.12%) lung carcinoma samples analyzed, ranking second to TP53. Significantly, BAF-mutated samples exhibited more genomic mutations than BAF wild-type ones. Moreover, a significant positive correlation existed between the BAF mutations and overall genomic mutations in these lung carcinoma samples (P<0.001, Pearson's correlation analysis). Specifically, the mutant-typing of 6 BAF genes, SMARCA4, ARID2, ARID1B, BCL11A, BCL11B and BRD9 was associated with more overall mutations in the lung carcinoma samples. A mutation reporter system was developed by means of the establishment of stable cell sublines with slippage-luciferase transcript in a lung adenocarcinoma cell line, Calu-3. SMARCA4, the most frequently mutated BAF gene in lung cancer, was stably knocked down by pSUPER constructs carrying short hairpin RNA (shRNA). Mutation ratios determined from the mutation reporters of Calu-3 cells were significantly increased upon stable SMARCA4 knockdown. We demonstrated that genetic mutations of BAF complexes lead to genome instability of lung carcinoma. Therefore, BAF complexes play an important role in maintaining genome stability in human lung cancer.
authors.affiliation: Department of Cardiothoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Huang
authors.affiliation: Department of Cardiothoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.
authors.forename: Shao-Mu
authors.initials: SM
authors.lastname: Chen
authors.affiliation: Department of Cardiothoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.
authors.forename: Liang-Bin
authors.initials: LB
authors.lastname: Pan
authors.affiliation: Department of Cardiothoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Cardiothoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Ma
mesh_terms: D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005787:Gene Frequency; D042822:Genomic Instability; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D059645:Mutation Rate; D009687:Nuclear Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: C501959:BANF1 protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases