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Chromatin Remodeling and Cancer
Research Guide
What is Chromatin Remodeling and Cancer?
Chromatin remodeling and cancer refers to the role of ATP-dependent chromatin remodeling complexes, such as SWI/SNF, and their mutations like ARID1A in regulating epigenetic access to DNA, tumor suppression, and oncogenic processes in various cancers.
This field encompasses 18,321 papers examining chromatin remodeling's impact on cancer development, progression, and epigenetic regulation. SWI/SNF complexes and ARID1A mutations disrupt nucleosome positioning, affecting gene expression and tumor suppression. Studies highlight synthetic lethality and oncogenic transformation linked to these alterations.
Topic Hierarchy
Research Sub-Topics
SWI/SNF Chromatin Remodeling Complexes in Cancer
This sub-topic studies the composition, regulation, and tumor-suppressive functions of SWI/SNF complexes across cancer types. Researchers investigate subunit mutations and their epigenetic consequences.
ARID1A Mutations in Oncogenic Transformation
This sub-topic examines ARID1A loss-of-function mutations in cancers like ovarian and endometrial, linking to enhancer dysregulation. Researchers use CRISPR models to dissect transformation mechanisms.
Epigenetic Regulation by Chromatin Remodelers
This sub-topic explores how chromatin remodeling enzymes control DNA methylation, histone variants, and accessibility in cancer epigenomes. Researchers map remodeler-histone interactions genome-wide.
Synthetic Lethality in Chromatin Remodeling Cancers
This sub-topic identifies paralog vulnerabilities and drug combinations exploiting SWI/SNF deficiencies. Researchers screen for ARID1A-mutant selective inhibitors like EZH2 blockers.
Genomic Analysis of Chromatin Remodeling Mutations
This sub-topic applies whole-genome sequencing to characterize mutational signatures and structural variants from remodeler loss. Researchers correlate mutations with transcriptional outcomes in TCGA cohorts.
Why It Matters
Mutations in chromatin remodeling genes drive cancer by altering epigenetic regulation and enabling oncogenic transformation, as seen in endometrial carcinoma where ∼25% of high-grade endometrioid tumors exhibit extensive copy number alterations and few DNA methylation changes (Getz, 2013, "Integrated genomic characterization of endometrial carcinoma"). In paediatric glioblastoma, driver mutations in histone H3.3 and chromatin remodelling genes contribute to tumor formation (Schwartzentruber et al., 2012, "Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma"). Breast cancer genomics reveal driver mutations in these pathways among somatic alterations conferring selective advantage (Stephens et al., 2012, "The landscape of cancer genes and mutational processes in breast cancer"). Colon and rectal cancer characterizations identify recurrent alterations in SWI/SNF components (The Cancer Genome Atlas Network, 2012, "Comprehensive molecular characterization of human colon and rectal cancer"). These findings support targeted therapies exploiting synthetic lethality in SWI/SNF-mutant cancers.
Reading Guide
Where to Start
"The Biology of Chromatin Remodeling Complexes" (Clapier and Cairns, 2009) provides foundational mechanisms of ATP-dependent remodeling, essential before diving into cancer-specific mutations.
Key Papers Explained
"The Biology of Chromatin Remodeling Complexes" (Clapier and Cairns, 2009) establishes SWI/SNF functions, which "Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma" (Schwartzentruber et al., 2012) applies to pediatric brain tumors. "Integrated genomic characterization of endometrial carcinoma" (Getz, 2013) builds on this by quantifying mutations in 373 cases, linking to copy number changes. "Comprehensive molecular characterization of human colon and rectal cancer" (The Cancer Genome Atlas Network, 2012) extends findings to gastrointestinal cancers, highlighting recurrent SWI/SNF alterations.
Paper Timeline
Most-cited paper highlighted in red. Papers ordered chronologically.
Advanced Directions
Current work emphasizes ARID1A mutations and synthetic lethality, as inferred from genomic patterns in top papers like Getz (2013) and Schwartzentruber et al. (2012). No recent preprints or news available, so frontiers remain in exploiting these for therapies in endometrial, glioblastoma, and colon cancers.
Papers at a Glance
| # | Paper | Year | Venue | Citations | Open Access |
|---|---|---|---|---|---|
| 1 | The 2007 WHO Classification of Tumours of the Central Nervous ... | 2010 | Digital Access to Scho... | 13.8K | ✓ |
| 2 | Comprehensive molecular characterization of human colon and re... | 2012 | Nature | 8.5K | ✓ |
| 3 | Integrated genomic characterization of endometrial carcinoma | 2013 | Nature | 5.6K | ✓ |
| 4 | Driver mutations in histone H3.3 and chromatin remodelling gen... | 2012 | Nature | 2.6K | ✕ |
| 5 | Prediction of central nervous system embryonal tumour outcome ... | 2002 | Nature | 2.4K | ✕ |
| 6 | SMARCAD1 ATPase activity is required to silence endogenous ret... | 2019 | Nature Communications | 2.4K | ✓ |
| 7 | The Biology of Chromatin Remodeling Complexes | 2009 | Annual Review of Bioch... | 2.3K | ✕ |
| 8 | The WHO Classification of Tumors of the Nervous System | 2002 | Journal of Neuropathol... | 1.9K | ✓ |
| 9 | CBTRUS Statistical Report: Primary brain and other central ner... | 2017 | Neuro-Oncology | 1.8K | ✓ |
| 10 | The landscape of cancer genes and mutational processes in brea... | 2012 | Nature | 1.7K | ✓ |
Frequently Asked Questions
What role do SWI/SNF complexes play in chromatin remodeling?
SWI/SNF complexes use ATP to reposition nucleosomes, exposing regulatory DNA elements for transcription and other processes. "The Biology of Chromatin Remodeling Complexes" (Clapier and Cairns, 2009) explains that nucleosomes occlude DNA but enable active regulation via remodeling. This activity is critical for gene expression control in normal and cancer cells.
How do ARID1A mutations contribute to cancer?
ARID1A mutations in SWI/SNF complexes impair tumor suppression and promote oncogenic transformation. These alterations appear in cancers like endometrial and colon types, disrupting epigenetic regulation. Genomic studies link them to copy number changes and synthetic lethality opportunities.
What is synthetic lethality in chromatin remodeling and cancer?
Synthetic lethality occurs when SWI/SNF mutations sensitize cancer cells to specific inhibitors, aiding targeted therapy. Papers in this cluster explore this in ARID1A-mutant tumors. It provides a strategy to selectively kill cancer cells while sparing normal ones.
Which cancers show chromatin remodeling gene mutations?
Paediatric glioblastoma features driver mutations in chromatin remodelling genes and histone H3.3 (Schwartzentruber et al., 2012). Endometrial carcinoma displays them in ∼25% of high-grade cases (Getz, 2013). Colon, rectal, and breast cancers also harbor these alterations.
How does chromatin remodeling affect mammalian development and cancer?
Chromatin remodeling regulates gene access during mammalian development, with disruptions leading to cancer. SMARCAD1 ATPase silences retroviruses in embryonic stem cells (Sachs et al., 2019, "SMARCAD1 ATPase activity is required to silence endogenous retroviruses in embryonic stem cells"). Mutations hijack these mechanisms for tumorigenesis.
What methods characterize chromatin remodeling in cancer?
Integrated genomic, transcriptomic, and proteomic analyses identify mutations, as in 373 endometrial carcinomas (Getz, 2013). Array- and sequencing-based technologies reveal copy number alterations and epigenetic changes. These approaches map driver mutations in breast and colon cancers.
Open Research Questions
- ? How do specific SWI/SNF subunit mutations differentially affect synthetic lethality across cancer types?
- ? What are the precise mechanisms by which ARID1A loss alters enhancer landscapes in high-grade endometrioid tumors?
- ? Can histone H3.3 and chromatin remodeling mutations in glioblastoma be targeted via epigenetic therapies?
- ? How does SMARCAD1-mediated retrovirus silencing intersect with oncogenic transformation in adult cancers?
- ? What copy number alteration patterns distinguish uterine serous from endometrioid endometrial carcinomas?
Recent Trends
The field includes 18,321 works with a focus on SWI/SNF and ARID1A in cancers like endometrial (∼25% high-grade cases with alterations, Getz, 2013) and glioblastoma (Schwartzentruber et al., 2012).
No growth rate, recent preprints, or news provided, indicating stable emphasis on genomic characterization from 2012-2013 papers.
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