Section 4: BAF in Cancer

Why are BAF complex subunits frequently mutated in cancer?

BAF complexes are critical for controlling gene expression, and their disruption can lead to aberrant transcription programs that drive oncogenesis.

Name four cancers or syndromes associated with mutations in BAF complex subunits.

Malignant Rhabdoid Tumours (SMARCB1), Synovial Sarcoma (SS18-SSX fusion), SCCOHT ovarian cancer (SMARCA4/SMARCA2), and Coffin-Siris syndrome (ARID1B).

What is the primary genetic driver event in Malignant Rhabdoid Tumours (MRT)?

Biallelic (homozygous) loss of SMARCB1 (also known as SNF5).

What is unusual about the mutational landscape of Malignant Rhabdoid Tumours?

They are remarkably genetically simple cancers, often having very few other mutations besides the loss of SMARCB1.

What happens when SMARCB1 is restored in an MRT cell line?

It restores the BAF complex to its correct genomic sites, re-activates enhancer features, restores accessibility, and halts cancer cell proliferation.

What is the role of PRC2 (Polycomb Repressive Complex 2) in MRT?

PRC2 activity is critical for the development and maintenance of MRT, as it provides an antagonistic repressive force to the lost BAF activity. Inhibiting PRC2 is a therapeutic strategy.

What is the genetic basis of Synovial Sarcoma?

It is driven by a fusion oncoprotein, most commonly SS18-SSX.

What does the SS18-SSX fusion do in Synovial Sarcoma?

The fusion protein relocates the BAF complex from its normal active sites to Polycomb-repressed target genes.

How does the SS18-SSX fusion protein drive cancer?

By redirecting BAF activity to the wrong genes, it drives aberrant transcription programs that promote oncogenic gene expression and cell proliferation.

What is the clinical significance of BRD9 in Synovial Sarcoma?

CRISPR screens revealed that Synovial Sarcoma cells are dependent on BRD9, and its degradation (e.g., by dBRD9 compound) reverses oncogenic gene expression and shows promise as a therapy.

What is a potential therapeutic strategy for cancers with SMARCA4 deletion?

Targeting the paralog SMARCA2, as cells often need at least one of these two subunits to survive (synthetic lethality).

In SCCOHT, what is the effect of restoring wild-type SMARCA4?

It restores chromatin accessibility at BAF target promoters and rescues