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Multi-omic alterations of the SWI/SNF complex define a clinical subgroup in lung adenocarcinoma.

ABSTRACT: SWI/SNF complexes are major targets of mutations in cancer. Here, we combined multiple "-omics" methods to assess SWI/SNF composition and aberrations in LUAD. Mutations in lung SWI/SNF subunits were highly recurrent in our LUAD cohort (41.4%), and over 70% of the mutations were predicted to have functional impact. Furthermore, SWI/SNF expression in LUAD suffered an overall repression that could not be explained exclusively by genetic alterations. Finally, SWI/SNF mutations were associated with poorer overall survival in TCGA-LUAD. We propose SWI/SNF-mutant LUAD as a separate clinical subgroup with practical implications.

SUBMITTER: Peinado P

PROVIDER: S-EPMC8931969 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Multi-omic alterations of the SWI/SNF complex define a clinical subgroup in lung adenocarcinoma.

Peinado Paola P Andrades Alvaro A Cuadros Marta M Rodriguez Maria Isabel MI Coira Isabel F IF Garcia Daniel J DJ Benitez-Cantos Maria S MS Cano Carlos C Zarzuela Eduardo E Muñoz Javier J Loidi Claudia C Saiz Monica M Medina Pedro P PP

Clinical epigenetics 20220317 1

SWI/SNF complexes are major targets of mutations in cancer. Here, we combined multiple "-omics" methods to assess SWI/SNF composition and aberrations in LUAD. Mutations in lung SWI/SNF subunits were highly recurrent in our LUAD cohort (41.4%), and over 70% of the mutations were predicted to have functional impact. Furthermore, SWI/SNF expression in LUAD suffered an overall repression that could not be explained exclusively by genetic alterations. Finally, SWI/SNF mutations were associated with p ...[more]

PMID: 35300733

Similar Datasets

Integrative multi-omic analysis of the SWI/SNF complex defines a new clinical subgroup of lung adenocarcinoma patients

Project description:Mammalian SWI/SNF complexes are ATP-dependent chromatin remodelers composed of varying combinations of subunits that, together, fine-tune transcriptional regulation and genome integrity. SWI/SNF complex subunits have been identified as major targets of mutations in several tumor types suggesting a relevant role in tumorigenesis. However, there is a lack of comprehensive studies of the whole SWI/SNF complex in lung adenocarcinoma (LUAD). Here, we combined genomic, transcriptomic, and proteomic approaches to identify which SWI/SNF subunits are present in lung cells, as well as their mutational status, mRNA levels, and protein levels in LUAD. For these purposes, we combined data from LUAD primary tumors, normal lung and LUAD cell lines, and external LUAD data from The Cancer Genome Atlas. Importantly, we found that mutations in the SWI/SNF complex in LUAD not only present a high incidence but we also observed that only the mutational status of the SWI/SNF complex and not the mutations in any of the top ten LUAD driver genes is associated with poorer overall survival in LUAD patients. Furthermore, we showed that the expression of the SWI/SNF complex in LUAD suffers an overall repression that cannot be explained exclusively by genetic alterations. Based on our findings, we propose that SWI/SNF-mutant LUAD tumors should be considered as a distinct subgroup with practical applications in the prognosis and follow-up of LUAD patients.

2022-04-01 | PXD017397 | Pride

Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer.

Project description:Defining the molecular genetic alterations underlying pancreatic cancer may provide unique therapeutic insight for this deadly disease. Toward this goal, we report here an integrative DNA microarray and sequencing-based analysis of pancreatic cancer genomes. Notable among the alterations newly identified, genomic deletions, mutations, and rearrangements recurrently targeted genes encoding components of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex, including all three putative DNA binding subunits (ARID1A, ARID1B, and PBRM1) and both enzymatic subunits (SMARCA2 and SMARCA4). Whereas alterations of each individual SWI/SNF subunit occurred at modest-frequency, as mutational "hills" in the genomic landscape, together they affected at least one-third of all pancreatic cancers, defining SWI/SNF as a major mutational "mountain." Consistent with a tumor-suppressive role, re-expression of SMARCA4 in SMARCA4-deficient pancreatic cancer cell lines reduced cell growth and promoted senescence, whereas its overexpression in a SWI/SNF-intact line had no such effect. In addition, expression profiling analyses revealed that SWI/SNF likely antagonizes Polycomb repressive complex 2, implicating this as one possible mechanism of tumor suppression. Our findings reveal SWI/SNF to be a central tumor suppressive complex in pancreatic cancer.

| S-EPMC3277150 | biostudies-literature

Comprehensive Analysis of SWI/SNF Inactivation in Lung Adenocarcinoma Cell Models.

Project description:Mammalian SWI/SNF (SWitch/Sucrose Non-Fermentable) complexes are ATP-dependent chromatin remodelers whose subunits have emerged among the most frequently mutated genes in cancer. Studying SWI/SNF function in cancer cell line models has unveiled vulnerabilities in SWI/SNF-mutant tumors that can lead to the discovery of new therapeutic drugs. However, choosing an appropriate cancer cell line model for SWI/SNF functional studies can be challenging because SWI/SNF subunits are frequently altered in cancer by various mechanisms, including genetic alterations and post-transcriptional mechanisms. In this work, we combined genomic, transcriptomic, and proteomic approaches to study the mutational status and the expression levels of the SWI/SNF subunits in a panel of 38 lung adenocarcinoma (LUAD) cell lines. We found that the SWI/SNF complex was mutated in more than 76% of our LUAD cell lines and there was a high variability in the expression of the different SWI/SNF subunits. These results underline the importance of the SWI/SNF complex as a tumor suppressor in LUAD and the difficulties in defining altered and unaltered cell models for the SWI/SNF complex. These findings will assist researchers in choosing the most suitable cellular models for their studies of SWI/SNF to bring all of its potential to the development of novel therapeutic applications.

| S-EPMC7763689 | biostudies-literature

The SWI/SNF complex regulates the expression of miR-222, a tumor suppressor microRNA in lung adenocarcinoma.

Project description:SWitch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes are key epigenetic regulators that are recurrently mutated in cancer. Most studies of these complexes are focused on their role in regulating protein-coding genes. However, here, we show that SWI/SNF complexes control the expression of microRNAs. We used a SMARCA4-deficient model of lung adenocarcinoma (LUAD) to track changes in the miRNome upon SMARCA4 restoration. We found that SMARCA4-SWI/SNF complexes induced significant changes in the expression of cancer-related microRNAs. The most significantly dysregulated microRNA was miR-222, whose expression was promoted by SMARCA4-SWI/SNF complexes, but not by SMARCA2-SWI/SNF complexes via their direct binding to a miR-222 enhancer region. Importantly, miR-222 expression decreased cell viability, phenocopying the tumor suppressor role of SMARCA4-SWI/SNF complexes in LUAD. Finally, we showed that the miR-222 enhancer region resides in a topologically associating domain that does not contain any cancer-related protein-coding genes, suggesting that miR-222 may be involved in exerting the tumor suppressor role of SMARCA4. Overall, this study highlights the relevant role of the SWI/SNF complex in regulating the non-coding genome, opening new insights into the pathogenesis of LUAD.

| S-EPMC9989735 | biostudies-literature

SWI/SNF Alterations in Squamous Bladder Cancers.

Project description:Dysfunction of the SWI/SNF complex has been observed in various cancers including urothelial carcinomas. However, the clinical impact of the SWI/SNF complex in squamous-differentiated bladder cancers (sq-BLCA) remains unclear. Therefore, we aimed to analyze potential expression loss and genetic alterations of (putative) key components of the SWI/SNF complex considering the co-occurrence of genetic driver mutations and PD-L1 expression as indicators for therapeutic implications. Assessment of ARID1A, SMARCA2, SMARCA4, SMARCB1/INI1, SMARCC1, SMARCC2 and PBRM1 mutations in a TCGA data set of sq-BLCA (n = 45) revealed that ARID1A was the most frequently altered SWI/SNF gene (15%) while being associated with protein downregulation. Genetic alterations and loss of ARID1A were confirmed by Targeted Next Generation Sequencing (NGS) (3/6) and immunohistochemistry (6/116). Correlation with further mutational data and PD-L1 expression revealed co-occurrence of ARID1A loss and TP53 mutations, while positive correlations with other driver mutations such as PIK3CA were not observed. Finally, a rare number of sq-BLCA samples were characterized by both ARID1A protein loss and strong PD-L1 expression suggesting a putative benefit upon immune checkpoint inhibitor therapy. Hence, for the first time, our data revealed expression loss of SWI/SNF subunits in sq-BLCA, highlighting ARID1A as a putative target of a small subgroup of patients eligible for novel therapeutic strategies.

| S-EPMC7699259 | biostudies-literature

Mammalian SWI/SNF Complex Genomic Alterations and Immune Checkpoint Blockade in Solid Tumors.

Project description:Prior data have variably implicated the inactivation of the mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) complex with increased tumor sensitivity to immune checkpoint inhibitors (ICI). Herein, we examined the association between mSWI/SNF variants and clinical outcomes to ICIs. We correlated somatic loss-of-function (LOF) variants in a predefined set of mSWI/SNF genes (ARID1A, ARID1B, SMARCA4, SMARCB1, PBRM1, and ARID2) with clinical outcomes in patients with cancer treated with systemic ICIs. We identified 676 patients from Dana-Farber Cancer Institute (DFCI, Boston, MA) and 848 patients from a publicly available database from Memorial Sloan Kettering Cancer Center (MSKCC, New York, NY) who met the inclusion criteria. Multivariable analyses were conducted and adjusted for available baseline factors and tumor mutational burden. Median follow-up was 19.6 (17.6-22.0) months and 28.0 (25.0-29.0) months for the DFCI and MSKCC cohorts, respectively. Seven solid tumor subtypes were examined. In the DFCI cohort, LOF variants of mSWI/SNF did not predict improved overall survival (OS), time-to-treatment failure (TTF), or disease control rate. Only patients with renal cell carcinoma with mSWI/SNF LOF showed significantly improved OS and TTF with adjusted HRs (95% confidence interval) of 0.33 (0.16-0.7) and 0.49 (0.27-0.88), respectively, and this was mostly driven by PRBM1 In the MSKCC cohort, where only OS was captured, LOF mSWI/SNF did not correlate with improved outcomes across any tumor subtype. We did not find a consistent association between mSWI/SNF LOF variants and improved clinical outcomes to ICIs, suggesting that mSWI/SNF variants should not be considered as biomarkers of response to ICIs.

| S-EPMC7415546 | biostudies-literature

SWI/SNF complex alterations as a biomarker of immunotherapy efficacy in pancreatic cancer.

Project description:BACKGROUNDImmune checkpoint inhibitors (ICIs) fail to demonstrate efficacy in pancreatic cancer. Recently, genomic biomarkers have been associated with response to ICIs: microsatellite instability high (MSI-H) and tumor mutation burden (TMB) > 10 mutations/Mb. Alterations in Switch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling genes may predispose to improved outcomes with immunotherapy. The current study examined a possible role for SWI/SNF complex abnormalities in pancreatic cancer responsiveness to ICIs.METHODSA database of 6831 cancer patients that had undergone next-generation sequencing (NGS) was filtered for advanced pancreatic cancer, SWI/SNF alterations, and outcomes depending on immunotherapy treatment.RESULTSNine patients had metastatic pancreatic adenocarcinoma harboring SWI/SNF chromatin remodeling gene alterations and had received ICIs: 7 had an ARID1A alteration (77%); 2, ARID1B (22%); 3, SMARCA4 (33%); 1, SMARCB1 (11%); and 1, PBRM1 (11%). Three patients possessed more than 1 SWI/SNF complex alteration. Only 3 tumors were microsatellite unstable. Eight of 9 patients (89%) achieved an objective response, including a complete remission, with the 2 longest responses ongoing at 33+ and 36+ months. Median progression-free and overall survival was 9 and 15 months, respectively. Responses occurred even in the presence of microsatellite stability, low TMB, and/or low PD-L1 expression.CONCLUSIONA small subset of patients with pancreatic cancer have genomic alterations in SWI/SNF chromatin remodeling components and appear to be responsive to ICIs, suggesting the need for prospective trials.TRIAL REGISTRATIONClinicalTrials.gov, NCT02478931.FUNDINGJoan and Irwin Jacobs Fund, NIH P30 CA023100 (RK) and LRP KYGF9753 (GPB), the Gershenson, Duarte, and anonymous patient families (GPB).

| S-EPMC8492298 | biostudies-literature

Mutational landscape of SWI/SNF complex genes reveal correlation to predictive biomarkers for immunotherapy sensitivity in lung adenocarcinoma patients.

Project description:BackgroundThe search for prognostic biomarkers indicating sensitivity to immunotherapy in lung adenocarcinoma patients has zeroed in on genes in the switch/sucrose non-fermentable (SWI/SNF) pathway. The mutational profiles of key genes are not clearly defined, however, and no comparisons have been conducted on whether mutations in the genes involved provide the same predictive value.MethodsIn this study, analysis of clinical factors, tumor mutation burden (TMB), chromosomal instability, and co-alterations was conducted for 4344 lung adenocarcinoma samples. Independent online cohorts (N = 1661 and 576) were used to supplement the analysis with survival and RNA-seq data.ResultsMutational burden and chromosomal instability analysis showed that ARID family mutations (including ARID1A, ARID1B, or ARID2 mutations) and SMARC family mutations (including SMARCA4 or SMARCB1 mutations) display different profiles from wild-type (WT) samples (TMB: ARID versus WT: P < 2.2 × 10-16, SMARC versus WT: P < 2.2 × 10-16; CIN: ARID versus WT: P = 1.8 × 10-5, SMARC versus WT: P = 0.027). Both mutant groups have a higher proportion of transversions than transitions, whereas the ratio is more equal for wild-type samples. Survival analysis shows that patients with ARID mutations were more sensitive to immunotherapy treatment than wild-type and SMARC-mutated patients (P < 0.001 and P = 0.013, respectively), and multivariate Cox analysis reveals that the presence of ARID mutations is likely the main cause.ConclusionsThe research presented in this study shows that mutations in the ARID gene family, including ARID1A, ARID1B, and ARID2, are primarily responsible for the sensitive response to immunotherapy treatment in patients with lung adenocarcinoma.

| S-EPMC10334452 | biostudies-literature

Architecture of SWI/SNF chromatin remodeling complex.

Project description: Not available

| S-EPMC6251806 | biostudies-literature

SWI/SNF Complex Alterations in Tumors with Rhabdoid Features: Novel Therapeutic Approaches and Opportunities for Adoptive Cell Therapy.

Project description:The SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex is one of the most remarkably altered epigenetic regulators in cancer. Pathogenic mutations in genes encoding SWI/SNF-related proteins have been recently described in many solid tumors, including rare and aggressive malignancies with rhabdoid features with no standard therapies in advanced or metastatic settings. In recent years, clinical trials with targeted drugs aimed at restoring its function have shown discouraging results. However, preclinical data have found an association between these epigenetic alterations and response to immune therapy. Thus, the rationale for immunotherapy strategies in SWI/SNF complex alteration-related tumors is strong. Here, we review the SWI/SNF complex and how its dysfunction drives the oncogenesis of rhabdoid tumors and the proposed strategies to revert this alteration and promising novel therapeutic approaches, including immune checkpoint inhibition and adoptive cell therapy.

| S-EPMC10342479 | biostudies-literature

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