Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities

Pierre, Roodolph St.; Kadoch, Cigall

doi:10.1016/j.gde.2017.02.004

Cited by 147 publications

(137 citation statements)

References 108 publications

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“…The percentage of carcinoma cases with actionable gene aberrations related to drug selection was greater (65.5%) than that of sarcoma cases (33.3%). These percentages for all types of tumor will be increased in future by developing drugs that target currently "undruggable" alterations, such as deleterious mutations in SWI/SNF chromatin regulator genes, [40][41][42] which are detected in tumors such as sarcoma. In addition, we classified several detected mutations in currently druggable genes as "variants of unknown significance" due to lack of biological and clinical evidence.…”

Section: Discussionmentioning

confidence: 99%

Feasibility and utility of a panel testing for 114 cancer‐associated genes in a clinical setting: A hospital‐based study

Ichikawa²,

et al. 2019

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Next‐generation sequencing ( NGS ) of tumor tissue (ie, clinical sequencing) can guide clinical management by providing information about actionable gene aberrations that have diagnostic and therapeutic significance. Here, we undertook a hospital‐based prospective study ( TOP ‐ GEAR project, 2nd stage) to investigate the feasibility and utility of NGS ‐based analysis of 114 cancer‐associated genes (the NCC Oncopanel test). We examined 230 cases (comprising more than 30 tumor types) of advanced solid tumors, all of which were matched with nontumor samples. Gene profiling data were obtained for 187 cases (81.3%), 111 (59.4%) of which harbored actionable gene aberrations according to the Clinical Practice Guidelines for Next Generation Sequencing in Cancer Diagnosis and Treatment (Edition 1.0) issued by 3 major Japanese cancer‐related societies. Twenty‐five (13.3%) cases have since received molecular‐targeted therapy according to their gene aberrations. These results indicate the utility of tumor‐profiling multiplex gene panel testing in a clinical setting in Japan. This study is registered with UMIN Clinical Trials Registry ( UMIN 000011141).

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Section: Discussionmentioning

confidence: 99%

Feasibility and utility of a panel testing for 114 cancer‐associated genes in a clinical setting: A hospital‐based study

Ichikawa²,

et al. 2019

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“…Both ARID1A and ARID2 encode components of SWI/SNF chromatin remodeling machinery, and their genetic alterations are also reported in other tumor types. 13 Because SWI/SNF machinery regulates chromatin conformation in an ATPdependent manner, their alterations are supposed to affect epigenetic changes in cancer cells; however, the biological roles of Therefore, its inactivation is largely complimentary to CTNNB1 activating mutations for WNT signal activation in HCC. 15 In contract to these well-characterized tumor suppressor genes, the biological roles of highly frequent mutations of ALB and APOB in HCC are uncertain.…”

Section: Reported Thatmentioning

confidence: 99%

Molecular genomic landscapes of hepatobiliary cancer

Shibata

Arai²,

Totoki³

2018

Cancer Science

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Hepatocellular carcinoma (HCC) and biliary tract cancer are more frequent in East Asia including Japan than in Europe or North America. A compilation of 1340 multi‐ethnic HCC genomes, the largest cohort ever reported, identified a comprehensive landscape of HCC driver genes, comprised of three core drivers (TP53,TERT, and WNT signaling) and combinations of infrequent alterations in various cancer pathways. In contrast, five core driver genes (TP53,ARID1A,KRAS,SMAD4, and BAP1) with characteristic molecular alterations including fusion transcripts involving fibroblast growth factor receptor 2 and the protein kinase A pathway, and IDH1/2 mutation constituted the biliary tract cancer genomes. Consistent with their heterogeneous epidemiological backgrounds, mutational signatures and combinations of non‐core driver genes within these cancer genomes were found to be complex. Integrative analyses of multi‐omics data identified molecular classifications of these tumors that are associated with clinical outcome and enrichments of potential therapeutic targets, including immune checkpoint molecules. Translating comprehensive molecular‐genomic analysis together with further basic research and international collaborations are highly anticipated for developing precise and better treatments, diagnosis, and prevention of these tumor types.

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“…The SWI/SNF complex (aka BAF complex) comprises more than 15 subunits and is involved in regulating gene expression largely through its ability to control nucleosome incorporation and chromatin remodeling at promoter sites . Loss of SMARCB1, a core member of the SWI/SNF complex, is the distinguishing genetic event that characterizes rhabdoid tumors.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of MYC attenuates tumor cell self‐renewal and promotes senescence in SMARCB1‐deficient Group 2 atypical teratoid rhabdoid tumors to suppress tumor growth in vivo

Alimova

Pierce

Danis

et al. 2019

Intl Journal of Cancer

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Loss of SMARCB1 is the hallmark genetic event that characterizes rhabdoid tumors in children. Rhabdoid tumors of the brain (ATRT) occur in young children and are particularly challenging with poor long term survival. SMARCB1 is a member of the SWI/SNF chromatin remodeling complex that is responsible for determining cellular pluripotency and lineage commitment. The mechanisms by which SMARCB1 deletion results in tumorigenesis remain unclear. Recent studies demonstrate that ATRT consists of 3 genomic sub-groups with a subset of poor outcome tumors expressing high BMP and MYC pathway activation. Here we show that MYC occupies distinct promoter loci in ATRT compared to embryonic stem (ES) cells. Further, using human ATRT cell lines, patient-derived cell culture, ex-vivo patient-derived tumor, and orthotopic xenograft models, we show that MYC inhibition is a molecular vulnerability in SMARCB1-deleted tumors and that such inhibition effectively suppresses BMP and pluripotency-associated genomic programs, attenuates tumor cell self-renewal, promotes senescence and inhibits ATRT tumor growth in vivo. Transgenic expression of Omomyc (a bona-fide MYC dominant negative) or chemical inhibition of MYC transcriptomic programs with the BET inhibitor JQ1 phenocopy genetic depletion of MYC, effectively restricting ATRT tumor growth and opening a promising therapeutic avenue for rhabdoid tumors in children. This article is protected by copyright. All rights reserved.

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Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities

Cited by 147 publications

References 108 publications

Feasibility and utility of a panel testing for 114 cancer‐associated genes in a clinical setting: A hospital‐based study

Feasibility and utility of a panel testing for 114 cancer‐associated genes in a clinical setting: A hospital‐based study

Molecular genomic landscapes of hepatobiliary cancer

Inhibition of MYC attenuates tumor cell self‐renewal and promotes senescence in SMARCB1‐deficient Group 2 atypical teratoid rhabdoid tumors to suppress tumor growth in vivo

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