Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer
Open accessAbstract
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.
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Both ARID1A and SMARCA4 are Switch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling complex genes that are important for epigenetic reprogramming in PDAC.
“Both ARID1A and SMARCA4 are Switch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling complex genes that are important for epigenetic reprogramming in PDAC63.”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [63]
Chromatin remodeling and SWI/SNF complex genes are among the most frequently altered classes of genes in PDAC and can occur via somatic deletions of associated chromosomal loci.
“Chromatin remodeling and SWI/SNF complex genes are one of the most frequently altered class of genes in PDAC45,48–50, and can occur via somatic deletions of the associated chromosomal loci94.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [94]
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- Authors
- Shain, A. H., Giacomini, C. P., Matsukuma, K., Karikari, C. A., Bashyam, M. D., Hidalgo, M., Maitra, A., & Pollack, J. R.
- Affiliations
- Stanford Medicine (US)
- Johns Hopkins University (US)
- Centre for DNA Fingerprinting and Diagnostics (IN)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-01-10
- Volume
- 109
- Issue
- 5
- Pages
- E252-9
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3277150
- OpenAlex
- W2126675803
- Cited by
- 221
- References
- 5
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 10 · 2023: 14 · 2022: 14 · 2021: 15 · 2020: 15 · 2019: 14 · 2018: 11 · 2017: 16 · 2016: 15 · 2015: 20 · 2014: 23 · 2013: 35 · 2012: 9
- FWCI
- 8.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Centre for DNA Fingerprinting and Diagnostics
- National Cancer Institute (R01CA113669, R01CA112016, P01CA134292, P50CA062924)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- SWI/SNF complex, pancreatic cancer, tumor suppression, SMARCA4, SMARCA2, ARID1A, ARID1B, PBRM1, genetic alterations, polycomb repressive complex 2, cellular senescence, cancer cell growth, mutational landscape
- MeSH terms
- Chromosomal Proteins, Non-Histone, Humans, Mutation, Pancreatic Neoplasms, Transcription Factors, Genes, Tumor Suppressor, Gene Expression Profiling, Chromatin Assembly and Disassembly, Transcriptome
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