title: Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer.
abstract: 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.
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA 94305, USA.
authors.forename: A Hunter
authors.initials: AH
authors.lastname: Shain
authors.forename: Craig P
authors.initials: CP
authors.lastname: Giacomini
authors.forename: Karen
authors.initials: K
authors.lastname: Matsukuma
authors.forename: Collins A
authors.initials: CA
authors.lastname: Karikari
authors.forename: Murali D
authors.initials: MD
authors.lastname: Bashyam
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Pollack
mesh_terms: D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D006801:Humans; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D059467:Transcriptome
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors