Neurosurgery notes/Tumours/Tumour genetics/SMARCA4 alterations

SMARCA4 alterations

View Details
Status
Done
logo
Parent item
Tumour genetics

General

  • Aka: BRG1-associated factors
  • SMARCA4 (SWI/SNF-related, matrix-associated, actin-dependent regulators of chromatin (SMARC) alteration

Gene loci

  • Chromosome 19p13.2.

Normal function

  • Encodes BRG1, the ATPase subunit of the SWI/SNF (BAF/PBAF) chromatin‑remodeling complex, which uses ATP hydrolysis to reposition or eject nucleosomes and regulate transcription, DNA repair, and cell‑cycle control.
  • Acts as a tumor suppressor by maintaining proper chromatin accessibility and transcriptional programs for differentiation and growth control.
notion image
notion image

Mutation effects

  • Two types
    • Class 1 mutations
      • Truncating mutations, fusions, and homozygous deletion (loss of function usually associated with protein loss)
        • Inactivating mutations, truncating variants, and deletions lead to loss of BRG1 protein, impaired ATPase activity, and defective chromatin remodeling, causing widespread transcriptional dysregulation.
        • BRG1 (or SMARCA4) is the most frequently mutated chromatin remodelling ATPase in cancer
    • Class 2 mutations
      • Missense mutations (postulated to have dominant negative or gain of function effects, but some reports suggest loss of function, especially in lung cancer)
      • Dominant-negative activity may be implicated in the context of a wild-type SMARCA4 allele (when present as heterozygous mutations) or dominant-negative activity with SMARCA2.
      • Missense SMARCA4 mutations can also result in loss of accessibility and loss of chromatin remodeling activity.
  • Germline loss‑of‑function variants cause dosage‑sensitive disruption of BAF complex function and developmental anomalies (Coffin–Siris spectrum, rhabdoid tumor predisposition).

Disease

  • Germline pathogenic variants predispose to atypical teratoid/rhabdoid tumor, and other rhabdoid tumors (rhabdoid tumor predisposition syndrome type 2).
    • Rhabdoid tumor predisposition syndrome (RTPS)
      • Significantly increased risk of rhabdoid tumors before the age of 3
      • Mutation
        • SMARCA4 variants: ~5% to 15% (RTPS2)
        • SMARCB1 variants: ~85%–95% (RTPS1)
      • Rhabdoid tumors
        • Location
          • Can occur in almost any location
          • Most commonly in the CNS; >50% in the cerebellum.
      • Other common locations:
        • Extracranial extrarenal malignant rhabdoid tumors (eMRT)
          • Heart, bladder, liver, retroperitoneum, head and neck, paravertebral muscles, mediastinum, pelvis; rhabdoid tumor of the kidney (RTK); and
          • SCCOHT (seen only in RTPS2, which is due to germline SMARCA4 alterations (and not in RTPS1 (with germline SMARCB1 alterations),
      • These highly aggressive cancers are designated rhabdoid because their cells look like rhabdomyoblasts, which are cells that are normally seen in embryos and develop into muscles.
      • 35% of pediatric malignant rhabdoid tumors are linked to germline SWI/SNF alterations
  • SMARCA4 alterations are also seen in subsets of lung carcinomas, medulloblastoma and other cancers, reflecting its role as a broadly relevant tumor suppressor.

Reference