SMARCB1/INI-1 and the SWI/SNF Complex

SMARCB1/INI-1 in Chordoma

The absence of SMARCB1/INI1 expression was originally thought to be specific to atypical teratoid/rhabdoid tumors (AT/RTs), but after researchers noted absence of expression in a number of other tumor types, SMARCB1 gained the attention of chordoma researchers. Studies have revealed that while most typical chordomas do express SMARCB1, loss of expression occurs more frequently in poorly differentiated and pediatric chordomas, suggesting that absence of this tumor suppressor may be important in especially aggressive chordomas.² This page contains a summary of published research exploring the role of the SMARCB1/INI-1 gene in chordoma.

• Molecular Evidence
• Clinical Evidence
• Open Clinical Trials

Molecular Evidence

Chromosome and Gene Abnormalities

• Losses of the region of chromosome 22 that harbors SMARCB1/INI-1 is common in chordomas ^{3 4 5 6} and deletion of the this locus specifically has been observed in poorly differentiated and pediatric chordomas.^{2 7 8 9 10 11 12 13 14}
• Poorly differentiated chordoma patients with SMARCB1/INI-1 loss have a significantly decreased mean overall survival compared to other chordoma subtypes.^{15 16}
• Upregulation of miR-671-5p and miR-193a-5p have been observed in SMARCB1/INI1-immunonegative cases and are thought to downregulate TGF-β signaling in pediatric chordoma.¹⁷
• MLPA and sequencing analysis of pediatric chordoma cases with loss of SMARCB1 protein showed 1 case of balletic SMARCB1 deletion and 2 cases with loss of one allele of SMARCB1.¹⁸

Somatic Mutations

• Two samples taken from the same patient at different anatomical locations each had the same nonsense mutations in SMARCB1 and CDKN2A (also implicated as a therapeutic target in chordoma).¹⁹
• Missense and nonsense mutations leading to loss of SMARCB1 protein expression were observed in 3 of 8 pediatric chordoma samples.¹⁹
• Targeted panel sequencing including SMARCB1 did not reveal any somatic mutations in a conventional chordoma patient.²⁰ Additional studies did not identify point mutations in any of the 9 SMARCB1/INI-1 exons.^{2 7 9}

Protein Expression

• SMARCB1/INI-1 is normally expressed in all tissues (chordoma and non-chordoma).²¹ Absence of expression is rare in chordomas, but it has been observed occasionally.²²
• Loss of expression is more frequent in pediatric chordomas than in adult chordomas ², and loss of expression is also more frequent in poorly differentiated chordomas.^{7 8 9 11 23} A 2016 study found loss of SMARCB1 expression in 4 of 8 pediatric samples tested, one of which was poorly differentiated.¹⁰
• Low expression of SMARCB1 (SNF5) was found to be associated with poor prognosis in skull base chordoma.²⁴
• SMARCB1 (BAF47) protein was lost in 4 poorly differentiated chordomas and in 3 classical/mixed chordomas within a pediatric chordoma cohort.¹⁸

Clinical Evidence

Case Study

• A pediatric patient with INI1-negative chordoma responded to conventional chemotherapy plus radiotherapy and remained alive 19 months after diagnosis.²⁵

Phase I Trial

• Tazemetostat: 2 INI-negative chordoma patients treated with the selective EZH2 inhibitor Tazemetostat had confirmed responses in the EZH-102 Phase I trial (NCT02601937).²⁶ One patient recorded an exceptional and durable response of 2+ years.²⁷

Open Clinical Trials

The following clinical trials have been launched to explore whether targeting EZH2 is effective in treating chordoma patients who have loss of INI-1. Visit our Clinical Trials page to view a list of other clinical trials available to chordoma patients and to find out who to contact if you wish to participate.