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SMARCB1 and SMARCA4 genes
Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.
Source updated: April 30, 2025 · Captured 2026-09-09.
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AT/RT was the first primary pediatric brain tumor in which a candidate tumor suppressor gene, SMARCB1, was identified.[73] SMARCB1 is genomically altered in most rhabdoid tumors, including CNS, renal, and extrarenal rhabdoid malignancies.[73] SMARCB1 is a component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex.[74]
Rare cases of rhabdoid tumors expressing SMARCB1 and lacking SMARCB1 variants have also been associated with somatic or germline variants of SMARCA4, another member of the SWI/SNF chromatin-remodeling complex.[75-77]
Less commonly, SMARCA4-negative (with retained SMARCB1) tumors have been described.[75-77] Loss of SMARCB1 or SMARCA4 staining is a defining marker for AT/RT.
The 2021 WHO classification defines AT/RT by the presence of either SMARCB1 or SMARCA4 alterations. Tumors with histological features of AT/RT that lack these genomic alterations are termed CNS embryonal tumors with rhabdoid features.[78]
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Despite the absence of recurring genomic alterations beyond SMARCB1 and SMARCA4,[79-81] biologically, relatively distinctive subsets of AT/RT have been identified.[82-84] In one study, three distinctive subsets of AT/RT were identified through the use of DNA methylation arrays for 150 AT/RT tumors and gene expression arrays for 67 AT/RT tumors:[83]
AT/RT tyrosinase (TYR): This subset represented approximately one-third of cases and was characterized by elevated expression of melanosomal markers such as TYR (the gene encoding tyrosinase). Cases in this subset were primarily infratentorial, with most presenting in children aged 0 to 1 year and showing chromosome 22q loss.[83] For patients with AT/RT TYR, the mean overall survival (OS) was 37 months in a clinically heterogeneous group (95% confidence interval [CI], 18–56 months).[85] In the prospective European Rhabdoid Registry (EU-RHAB) series, patients aged 1 year and older with AT/RT TYR demonstrated a 5-year OS rate of 71%, while those younger than 1 year with a non-TYR AT/RT had a very poor survival rate.[86]
AT/RT sonic hedgehog (SHH): This subset represented approximately 40% of cases and was characterized by elevated expression of genes in the SHH pathway (e.g., GLI2 and MYCN). Cases in this subset occurred with similar frequency in the supratentorium and infratentorium. While most patients presented before the age of 2 years, approximately one-third of patients presented between the ages of 2 and 5 years.[83] For patients with AT/RT SHH, the mean OS was 16 months (95% CI, 8–25 months).[85]In a subsequent study, the AT/RT SHH subgroup was further divided into three subtypes: SHH-1A, SHH-1B, and SHH-2.[87] Children older than 3 years who harbored the SHH-1B signature experienced the most favorable outcomes.
AT/RT MYC: This subset represented approximately one-fourth of cases and was characterized by elevated expression of MYC. AT/RT MYC cases tended to occur in the supratentorial compartment. While most AT/RT MYC cases occurred by the age of 5 years, AT/RT MYC represented the most common subset diagnosed at age 6 years and older. Focal deletions of SMARCB1 were the most common mechanism of SMARCB1 loss for this subset.[83] For patients with AT/RT MYC, the mean OS was 13 months (95% CI, 5–22 months).[85]
Loss of SMARCB1 or SMARCA4 protein expression has therapeutic significance, because this loss creates a dependence of the cancer cells on EZH2 activity.[88] Preclinical studies have shown that some AT/RT xenograft lines with SMARCB1 loss respond to EZH2 inhibitors with tumor growth inhibition and occasional tumor regression.[89,90] In a study of the EZH2 inhibitor tazemetostat, objective responses were observed in adult patients whose tumors had either SMARCB1 or SMARCA4 loss (non-CNS malignant rhabdoid tumors and epithelioid sarcoma).[91] For more information, see the Treatment of Recurrent Childhood CNS Atypical Teratoid/Rhabdoid Tumor section.
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For information about the treatment of childhood CNS AT/RTs, see Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumors Treatment.
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Publication references
Read the original reference and check its publication notices.
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Preserved source evidence · Independent clinical review pending · Not medical advice