Abstract 3930: Integrative genomic analysis reveals SWI/SNF chromatin remodeling complex to be a TGFβ-mediating tumor suppressor pathway in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer deaths in the developed world. A more complete characterization of molecular alterations may suggest new avenues for targeted therapy. Here we report the high-resolution genomic and transcriptional profiling of seventy PDAC early-passage tumor xenografts and cell lines – the largest PDAC dataset currently available of this sample size and resolution. Notable among novel loci, genomic deletion/mutation frequently targeted components of the SWI/SNF chromatin remodeling complex, including ARID1A, ARID1B, PBRM1, SMARCA2 and SMARCA4. Overall, focal deletion/mutation of a SWI/SNF component occurred in at least one-third of all PDAC specimens. In cell culture, RNAi-mediated knockdown of SWI/SNF subunits enhanced cell growth, growth-factor independence, and resistance to TGFβ growth-inhibition. Previously, SWI/SNF was reported to mediate TGFβ signaling. Remarkably, we found that five of the top ten SWI/SNF-mediated TGFβ-downregulated genes were focally amplified (MYC, BIRC3, PARD6B, KLF5, and CEBPD), while two of the top ten upregulated genes were focally deleted (PPAP2B, TNC), implying that its role in TGFβ growth-inhibitory signaling drives SWI/SNF loss in PDAC. In summary, we report the SWI/SNF chromatin remodeling complex, likely through mediating TGFβ signaling, to be a major tumour suppressor pathway in PDAC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3930. doi:10.1158/1538-7445.AM2011-3930