SMARCB1 Loss and Rhabdoid Tumours

A Cancer With Almost No Mutations

Rhabdoid tumours have one of the lowest mutation burdens of any human cancer. In most cases the only recurrent genetic event is loss of both SMARCB1 alleles, demonstrating that disabling a single chromatin-remodelling subunit can be sufficient to drive an aggressive malignancy.

SWI/SNF complexes use ATP to reposition nucleosomes and keep enhancers of differentiation genes accessible. Without SMARCB1, the complex cannot maintain these enhancers, and cells are held in a proliferative, undifferentiated state.

The Predisposition Syndrome

A substantial minority of children with rhabdoid tumours carry a germline SMARCB1 (or, rarely, SMARCA4) variant, causing rhabdoid tumour predisposition syndrome. These children tend to present younger and can develop tumours at more than one site.

Because of this, germline testing is recommended for children diagnosed with a rhabdoid tumour, and affected families are offered genetic counselling and surveillance.

The EZH2 Dependency

SMARCB1-deficient cells rely on the opposing activity of the PRC2 complex, and specifically on EZH2, to maintain their repressive chromatin state. This synthetic-lethal relationship is the basis for testing EZH2 inhibitors in rhabdoid tumours and the related SMARCB1-deficient epithelioid sarcoma, where tazemetostat is approved.

Loss of SMARCB1 (INI1) staining by immunohistochemistry is the standard diagnostic test.

Testing Pathway and Treatment Reality

The diagnostic sequence is loss of SMARCB1 (INI1) staining on immunohistochemistry, confirmation of biallelic SMARCB1 loss by sequencing or copy-number analysis, and then germline testing to identify rhabdoid tumour predisposition syndrome. SMARCA4 (BRG1) staining is added when SMARCB1 is retained but the histology still suggests a rhabdoid tumour.

Standard treatment remains intensive multimodal therapy — surgery, chemotherapy and, where appropriate, radiotherapy — because outcomes with the EZH2 inhibitor tazemetostat as a single agent have been modest in rhabdoid tumours specifically and better in epithelioid sarcoma. Trials are testing tazemetostat in combination and earlier in the course.

Key Takeaways

• ·Rhabdoid tumours are driven mainly by biallelic SMARCB1 loss in an otherwise near-silent genome.
• ·Germline SMARCB1 variants cause a predisposition syndrome, so germline testing is advised.
• ·SMARCB1 loss creates an EZH2 dependency exploited by EZH2 inhibitors in related tumours.