Abstract LB-130: Abnormal expression of SWI/SNF chromatin remodeling complex genes in lung cancer
Bibliographic record
Abstract
Abstract Objective: To study deregulation of the SWI/SNF chromatin remodeling complex in lung cancer tumors and cell lines with the emphasis on SMARCA2, SMARCA4 and ARID1A. Background: The DNA in each mammalian cell is compacted about 5000 fold into chromatin, and in the compacted state is unavailable for transcription. This compaction is controlled by three mechanisms: including the ATP-dependent chromatin remodeling complex SWI/SNF, consisting of 20 genes that code for about 12 protein subunits (some of which can substitute for each other). There are over 280 possible subunit permutations, influencing transcription, chromatin binding and remodeling, and tissue and gene specificity. Several subunit genes function as tumor suppressor genes (TSGs) including the interchangeable ATP catalytic components SMARCA2 (protein = BRM) and SMARCA4 (protein = BRG1) and the ARID1A (protein = BAF250a) accessory gene. The catalytic components are known to be inactivated in several cancers including lung, and ARID1A in ovarian cancer. Materials and Methods: Up to 58 cell lines and 60 non small cell lung cancer tumors arising in smokers and never smokers were studied. NextGen and Sanger sequencing of the SWI/SNF complex genes were performed on the cell lines. Western blots of nuclear extracts, methylation and qPCR were also performed on cell lines. Genome wide gene copy number (by SNP analyses) and microarray expression studies were performed on the tumors and cell lines. Immunostaining (for BRG1 and BAF250a) were performed on lung cancer microarrays. Results: Mutations rates in NSCLC lines were: SMARCA4 28% (mainly homozygous deletions), SMARCA2 0%, ARID1A 11% (mainly heterozygous point mutations). However, a marked decrease in nuclear protein expression was frequently present in NSCLC lines: BRG1 28%, BRM 28%, BAF250a 31%. Loss of BRG1, BRM, or BAF250a was present in 41% of the NSCLC lines, and 16% had loss of two or three. Combined analyses with microarray expression, immunostaining and qPCR studies of these three genes indicated frequent low expression in both NSCLC tumors and cell lines. In addition, DNA copy number by SNP analyses of NSCLC tumors indicated widespread loss of alleles of multiple members of the SWI/SNF complex. Evidence for epigenetic inactivation of one or more complex genes was present. Conclusions: Our data indicate frequent inactivation of one or more members of the SWI/SNF complex by a variety of mechanisms including deletions, mutations, epigenetic, transcriptional and translational control. The predicted downstream effects on transcription and histone regulation are likely to be widespread and possibly demonstrating cell type and gene specific effects. Although highly complicated, elucidation of the precise chromatin complex abnormalities, mechanisms and downstream effects indicate the possibility of multiple new therapeutic targets for lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-130. doi:10.1158/1538-7445.AM2011-LB-130
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".