[Show abstract][Hide abstract] ABSTRACT: Osteosarcoma is the most common primary bone tumor, yet there have been no substantial advances in treatment or survival in three decades. We examined 59 tumor/normal pairs by whole-exome, whole-genome, and RNA-sequencing. Only the TP53 gene was mutated at significant frequency across all samples. The mean nonsilent somatic mutation rate was 1.2 mutations per megabase, and there was a median of 230 somatic rearrangements per tumor. Complex chains of rearrangements and localized hypermutation were detected in almost all cases. Given the intertumor heterogeneity, the extent of genomic instability, and the difficulty in acquiring a large sample size in a rare tumor, we used several methods to identify genomic events contributing to osteosarcoma survival. Pathway analysis, a heuristic analytic algorithm, a comparative oncology approach, and an shRNA screen converged on the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway as a central vulnerability for therapeutic exploitation in osteosarcoma. Osteosarcoma cell lines are responsive to pharmacologic and genetic inhibition of the PI3K/mTOR pathway both in vitro and in vivo.
Cancer Research 12/2014; 74(20 Supplement). DOI:10.1073/pnas.1419260111 · 9.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cancer genome sequencing efforts have revealed the novel theme that chromatin modifiers are frequently mutated across a wide spectrum of cancers. Mutations in genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are particularly prevalent, occurring in 20% of all human cancers. As these are typically loss-of-function mutations and not directly therapeutically targetable, central goals have been to elucidate mechanism and identify vulnerabilities created by these mutations. Here, we discuss emerging data that these mutations lead to the formation of aberrant residual SWI/SNF complexes that constitute a specific vulnerability and discuss the potential for exploiting these dependencies in SWI/SNF mutant cancers.
Cancer Cell 09/2014; 26(3):309-317. DOI:10.1016/j.ccr.2014.07.018 · 23.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: SMARCB1 (INI1/SNF5/BAF47), a core subunit of the SWI/SNF (BAF) chromatin-remodeling complex, is inactivated in the large majority of rhabdoid tumors and germline heterozygous SMARCB1 mutations form the basis for rhabdoid predisposition syndrome. Mouse models validated Smarcb1 as a bona fide tumor suppressor as Smarcb1 inactivation in mice results in 100% of the animals rapidly developing cancer. SMARCB1 was the first subunit of the SWI/SNF complex found mutated in cancer. More recently, at least seven other genes encoding SWI/SNF subunits have been identified as recurrently mutated in cancer. Collectively, 20% of all human cancers contain a SWI/SNF mutation. Consequently, investigation of the mechanisms by which SMARCB1 mutation causes cancer has relevance not only for rhabdoid tumors, but also potentially for the wide variety of SWI/NSNF mutant cancers. Here we discuss normal functions of SMARCB1 and the SWI/SNF complex as well as mechanistic and potentially therapeutic insights that have emerged.
Cancer Genetics 09/2014; 207(9). DOI:10.1016/j.cancergen.2014.04.004 · 2.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent studies have revealed that ARID1A, encoding AT-rich interactive domain 1A (SWI-like), is frequently mutated across a variety of human cancers and also has bona fide tumor suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. Here, using a broad screening approach, we identify ARID1B, an ARID1A homolog whose gene product is mutually exclusive with ARID1A in SWI/SNF complexes, as the number 1 gene preferentially required for the survival of ARID1A-mutant cancer cell lines. We show that loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation in both cancer cells and primary cells. We also find that ARID1A and ARID1B are frequently co-mutated in cancer but that ARID1A-deficient cancers retain at least one functional ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. The results further identify ARID1B as a potential therapeutic target for ARID1A-mutant cancers.
Nature medicine 02/2014; 74(19 Supplement). DOI:10.1038/nm.3480 · 28.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Defects in epigenetic regulation play a fundamental role in the development of cancer, and epigenetic regulators have recently emerged as promising therapeutic candidates. We therefore set out to systematically interrogate epigenetic cancer dependencies by screening an epigenome-focused deep-coverage design shRNA (DECODER) library across 58 cancer cell lines. This screen identified BRM/SMARCA2, a DNA-dependent ATPase of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex, as being essential for the growth of tumor cells that harbor loss of function mutations in BRG1/SMARCA4. Depletion of BRM in BRG1-deficient cancer cells leads to a cell cycle arrest, induction of senescence, and increased levels of global H3K9me3. We further demonstrate the selective dependency of BRG1-mutant tumors on BRM in vivo. Genetic alterations of the mSWI/SNF chromatin remodeling complexes are the most frequent among chromatin regulators in cancers, with BRG1/SMARCA4 mutations occurring in ∼10-15% of lung adenocarcinomas. Our findings position BRM as an attractive therapeutic target for BRG1 mutated cancers. Because BRG1 and BRM function as mutually exclusive catalytic subunits of the mSWI/SNF complex, we propose that such synthetic lethality may be explained by paralog insufficiency, in which loss of one family member unveils critical dependence on paralogous subunits. This concept of "cancer-selective paralog dependency" may provide a more general strategy for targeting other tumor suppressor lesions/complexes with paralogous subunits.
Proceedings of the National Academy of Sciences 02/2014; 111(8). DOI:10.1073/pnas.1316793111 · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Collectively, genes encoding subunits of the SWI/SNF (BAF) chromatin remodeling complex are mutated in 20% of all human cancers, with the SMARCA4 (BRG1) subunit being one of the most frequently mutated. The SWI/SNF complex modulates chromatin remodeling through the activity of two mutually exclusive catalytic subunits, SMARCA4 and SMARCA2 (BRM). Here, we show that a SMARCA2-containing residual SWI/SNF complex underlies the oncogenic activity of SMARCA4-mutant cancers. We demonstrate that a residual SWI/SNF complex exists in SMARCA4-mutant cell lines and serves essential roles in cellular proliferation. Further, using data from loss-of-function screening of 165 cancer cell lines, we identify SMARCA2 as an essential gene in SMARCA4-mutant cancer cell lines. Mechanistically, we reveal that Smarca4 inactivation leads to greater incorporation of the non-essential SMARCA2 subunit into the SWI/SNF complex. Collectively, these results reveal a role for SMARCA2 in oncogenesis caused by SMARCA4 loss and identify the ATPase and bromodomain-containing SMARCA2 as a potential therapeutic target in these cancers.
[Show abstract][Hide abstract] ABSTRACT: In this issue of Cancer Cell, Wang and colleagues report that CARM1, a protein arginine methyltransferase, specifically methylates BAF155/SMARCC1, a core subunit of the SWI/SNF chromatin remodeling/tumor suppressor complex. This modification facilitates the targeting of BAF155 to genes of the c-Myc pathway and enhances breast cancer progression and metastasis.
Cancer cell 01/2014; 25(1):3-4. DOI:10.1016/j.ccr.2013.12.017 · 23.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genes encoding subunits of the SWI/SNF chromatin-remodeling complex constitute, collectively, one of the most frequently mutated targets in cancer. Although mutations in SWI/SNF genes are uncommon in prostate cancer, a new study shows that SChLAP1, a long noncoding RNA frequently expressed in aggressive prostate tumors, drives cancer by directly disrupting SNF5, a core subunit of the SWI/SNF complex.
[Show abstract][Hide abstract] ABSTRACT: Malignant rhabdoid tumors (MRTs) are aggressive pediatric cancers arising in brain, kidney and soft tissues, which are characterized by loss of the tumor suppressor SNF5/SMARCB1. MRTs are poorly responsive to chemotherapy and thus a high unmet clinical need exists for novel therapies for MRT patients. SNF5 is a core subunit of the SWI/SNF chromatin remodeling complex which affects gene expression by nucleosome remodeling. Here, we report that loss of SNF5 function correlates with increased expression of fibroblast growth factor receptors (FGFRs) in MRT cell lines and primary tumors and that re-expression of SNF5 in MRT cells causes a marked repression of FGFR expression. Conversely, siRNA-mediated impairment of SWI/SNF function leads to elevated levels of FGFR2 in human fibroblasts. In vivo, treatment with NVP-BGJ398, a selective FGFR inhibitor, blocks progression of a murine MRT model. Hence, we identify FGFR signaling as an aberrantly activated oncogenic pathway in MRTs and propose pharmacological inhibition of FGFRs as a potential novel clinical therapy for MRTs.
PLoS ONE 10/2013; 8(10):e77652. DOI:10.1371/journal.pone.0077652 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: SWI/SNF chromatin remodeling complexes are pleomorphic multi-subunit cellular machines that utilize the energy of ATP hydrolysis to modulate chromatin structure. The complexes interact with transcription factors at promoters and enhancers to modulate gene expression and contribute to lineage specification, differentiation and development. Initial clues to a role in tumor suppression for SWI/SNF complexes came over a decade ago when the gene encoding the SMARCB1/SNF5 core subunit was found specifically inactivated in nearly all pediatric rhabdoid tumors. In the last 3 years, cancer genome sequencing efforts have revealed an unexpectedly high mutation rate of SWI/SNF subunit genes, which are collectively mutated in 20% of all human cancers and approach the frequency of p53 mutations. Here we provide a background on these newly recognized tumor suppressor complexes, discuss mechanisms implicated in the tumor suppressor activity, and highlight findings that may lead to potential therapeutic targets for SWI/SNF mutant cancers.
Clinical Cancer Research 10/2013; 20(1). DOI:10.1158/1078-0432.CCR-13-0280 · 8.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this issue of Cell Stem Cell, Feng et al. (2013) report that the gene mutated in human CHARGE syndrome, ATP-dependent chromatin remodeling factor CHD7, contributes to the control of neurogenesis. The authors also report that exercise ameliorates these defects and suggest it as an intervention worthy of study in CHARGE syndrome.
[Show abstract][Hide abstract] ABSTRACT: Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer. These studies involve the sequencing of matched tumour-normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour-normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer.
[Show abstract][Hide abstract] ABSTRACT: Precise nucleosome-positioning patterns at promoters are thought to be crucial for faithful transcriptional regulation. However, the mechanisms by which these patterns are established, are dynamically maintained, and subsequently contribute to transcriptional control are poorly understood. The switch/sucrose non-fermentable chromatin remodeling complex, also known as the Brg1 associated factors complex, is a master developmental regulator and tumor suppressor capable of mobilizing nucleosomes in biochemical assays. However, its role in establishing the nucleosome landscape in vivo is unclear. Here we have inactivated Snf5 and Brg1, core subunits of the mammalian Swi/Snf complex, to evaluate their effects on chromatin structure and transcription levels genomewide. We find that inactivation of either subunit leads to disruptions of specific nucleosome patterning combined with a loss of overall nucleosome occupancy at a large number of promoters, regardless of their association with CpG islands. These rearrangements are accompanied by gene expression changes that promote cell proliferation. Collectively, these findings define a direct relationship between chromatin-remodeling complexes, chromatin structure, and transcriptional regulation.
Proceedings of the National Academy of Sciences 05/2013; 110(25). DOI:10.1073/pnas.1302209110 · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The discovery of biallelic, inactivating SMARCB1 mutations in rhabdoid tumors (RTs) over a decade ago represented the first recognized link between chromatin remodeling and tumor suppression. SMARCB1 is a core subunit of the SWI/SNF chromatin remodeling complex, and the recent emergence of frequent mutations in genes that encode subunits of this complex across a wide variety of cancers suggests that perturbation of this chromatin remodeling complex constitutes a key driver of cancer formation. Despite the highly aggressive nature of RTs, they are genetically simple cancers that appear to lack chromosomal instability and contain very few mutations. Indeed, the mutation rate in RTs is among the lowest of all cancers sequenced, with loss of SMARCB1 as essentially the sole recurrent event. Given the genetic simplicity of this disease, understanding the chromatin dysregulation caused by SMARCB1 loss may provide more general insight into how epigenetic alterations can contribute to oncogenic transformation and may reveal opportunities for targeted therapy not only of RT but also the variety of other SWI/SNF mutant cancers.
[Show abstract][Hide abstract] ABSTRACT: Although disordered chromatin organization has long been recognized as a feature of cancer, the molecular underpinnings of chromatin structure, epigenetic regulation, and their relationships to transcription are only beginning to be understood. Cancer genome sequencing studies have revealed a novel theme: frequent mutation of epigenetic regulators. Among these, the ARID1A/BAF250A subunit of the SWI/SNF (BRG1-associated factors) chromatin remodeling complex has emerged as recurrently mutated in a broad array of tumor types. We review the genomic and functional data supporting classification of ARID1A as a tumor suppressor.
Cancer Discovery 12/2012; DOI:10.1158/2159-8290.CD-12-0361 · 19.45 Impact Factor