Dataset Information

Inactivating mutations in genes encoding for components of the BAF/PBAF complex and immune-checkpoint inhibitor outcome.

ABSTRACT: Alterations of genes encoding subunits of the BAF/PBAF complexes are among the most frequent gene aberrations in human cancer. Such alterations have been shown to have an impact on tumor microenvironnement and on the capacity of tumors to respond to immune-checkpoint inhibitors (ICI). We analysed the clinical and genetic data from 43,728 patients accessed through cBioportal. The mutational frequencies of ARID1A, ARID1B, ARID2, PBRM1, SMARCA4, and SMARCB1 were 6.6%, 3,4, 3.4, 3.2, 4.1, and 1.2%, respectively. We then investigated the association between the presence of least one nonsynonymous somatic mutation of ARID1A, ARID1B, ARID2, PBRM1, SMARCA4, or SMARCB1 and overall survival of 1661 patients treated with an ICI. Across the entire cohort, patients with BAF/PBAF mutated tumors have a statistically significant improvement in overall survival (median overall survival: 28 months [95% CI 21.6-34.3] versus 15 months [95% CI 12.9-17.0], p < 0.0001). When tumor mutational burden was adjusted for a multivariable Cox regression analysis, BAF/PBAF gene mutations remained an independent prognostic factor for overall survival in patients treated ICI. Our results establish a relationship between mutations in key genes encoding for components of the BAF/PBAF complex and outcome of patients treated with ICI. Further studies are needed to elucidate the underlying mechanisms of this interaction.

SUBMITTER: Courtet K

PROVIDER: S-EPMC7366303 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Inactivating mutations in genes encoding for components of the BAF/PBAF complex and immune-checkpoint inhibitor outcome.

Courtet Kevin K Laizet Yec'han Y Lucchesi Carlo C Bessede Alban A Italiano Antoine A

Biomarker research 20200716

Alterations of genes encoding subunits of the BAF/PBAF complexes are among the most frequent gene aberrations in human cancer. Such alterations have been shown to have an impact on tumor microenvironnement and on the capacity of tumors to respond to immune-checkpoint inhibitors (ICI). We analysed the clinical and genetic data from 43,728 patients accessed through cBioportal. The mutational frequencies of ARID1A, ARID1B, ARID2, PBRM1, SMARCA4, and SMARCB1 were 6.6%, 3,4, 3.4, 3.2, 4.1, and 1.2%, ...[more]

PMID: 32695398

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Project description:Human and mouse somatic cells can be reprogrammed by the combination of Oct4, Sox2, Klf4, and c-Myc, but the efficiency of reprogramming is low. To better understand the process of reprogramming we sought to identify factors that mediate reprogramming at higher efficiency. For this we established an assay to screen nuclear fractions from the extracts of pluripotent cells based on Oct4 reactivation. We identified components of the ATP-dependent SWI/SNF chromatin-remodeling complex, which when used along with the above four factors increase reprogramming efficiency by five-fold and improve the quality of the reprogrammed cells. These cells were found to be capable of germline transmission and exhibited pluripotency according to gene expression and in vivo and in vitro assays. SWI/SNF was found to replace c-Myc and mediate its effects by facilitating recruitment of Oct4 on target promoters during reprogramming. Thus, somatic cell reprogramming using chromatin-remodeling molecules represents an efficient method of generating reprogrammed cells. DNA-free RNA samples to be hybridized on Illumina expression BeadChips were processed using a linear amplification kit (Ambion) (generating IVT duration: 12h). cRNA samples were quality-checked on a 2100 Bioanalyzer (Agilent) and hybridized as biological triplicates onto MouseWG-6 V2 chips as recommended and using materials / reagents provided by the manufacturer (hybridization time: 18h). The Myc probe on the V2 arrays was found to be defective. The bead intensities were mapped to gene information using BeadStudio 3.2 (Illumina), background correction was performed using the Affymetrix Robust Multi-array Analysis (RMA) background correction model, variance stabilization was performed using log2 scaling, and gene expression normalization was calculated with the quantile method implemented in the lumi package of R-Bioconductor. Data post-processing and graphics were performed with in-house developed functions in Matlab. Hierarchical clusters of genes and samples were performed with a one minus correlation metric and the average (unweighted pair group) linkage method. 4 samples were analyzed, each one them by triplicate. ESC: Mouse Embryonic Stem Cells (OG2 mix female and male) MEF: Mouse Embryonic Fibroblasts (OG2 male) iPS4F: Mouse induced Pluripotent Stem cells with 4 factors (Oct4, Sox2, Klf4, c-myc) iPS6F: Mouse induced Pluripotent Stem cells with 6 factors (Oct4, Sox2, Klf4, c-myc, Brg1, Baf155)

Dataset Information

Inactivating mutations in genes encoding for components of the BAF/PBAF complex and immune-checkpoint inhibitor outcome.

Publications

Inactivating mutations in genes encoding for components of the BAF/PBAF complex and immune-checkpoint inhibitor outcome.

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