Shain, A.H. and Giacomini, C.P. and Matsukuma, K. and Karikari, C.A. and Bashyam, M.D. and Hidalgo, M. and Maitra, A. and Pollack, J.R. (2012) Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer. Proceedings of the National Academy of Sciences, 109 (5). E252-E259. ISSN 0027-8424

Preview

Text PNAS 109 e252.pdf Download (1558Kb) | Preview

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.

Item Type:	Article
Depositing User:	Users 2 not found.
Date Deposited:	04 Sep 2015 07:32
Last Modified:	04 Sep 2015 07:32
URI:	http://cdfd.sciencecentral.in/id/eprint/470

Actions (login required)

View Item