Mechanisms by which SMARCB1 loss drives rhabdoid tumor growth.
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/SNF 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.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA, USA.
Kimberly H
KH
Kim
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA, USA. Electronic address: Charles_Roberts@dfci.harvard.edu.
Charles W M
CW
Roberts
D000818:Animals; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000096:biosynthesis / Q000235:genetics*; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D051379:Mice; D009154:Mutation; D009707:Nucleosomes / Q000235:genetics; D018335:Rhabdoid Tumor / Q000235:genetics* / Q000473:pathology*; D000071796:SMARCB1 Protein; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D009707:Nucleosomes; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4
Rhabdoid tumor; SMARCB1; SNF5; SWI/SNF; chromatin-remodeling complex