Chordoma Foundation

SMARCB1/INI-1 and the SWI/SNF Complex

SMARCB1/INI-1 in Chordoma

SMARCB1 (also known as INI-1, SNF5, or BAF47) is a member of the ATP-dependent SWI/SNF chromatin-remodeling complex, which regulates gene expression by influencing the way that DNA is packaged.

Location: SMARCB1/INI-1, Chromosome 22q11.2

The SMARCB1/INI-1 gene is expressed in normal tissues and is thought to function as a tumor suppressor. Loss of expression as a result of deletions or other gene abnormalities has been associated with the pathogenesis of rhabdoid tumors.1

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

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.

Trial Identifier



NCT02601950 A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma 33 trial locations around the world



Bourdeaut F, Lequin D, Brugières L, et al. Frequent hSNF5/INI1 germline mutations in patients with rhabdoid tumor. Clin Cancer Res. 2011;17(1):31-38.
Yadav R, Sharma M, Malgulwar P, et al. Prognostic value of MIB-1, p53, epidermal growth factor receptor, and INI1 in childhood chordomas. Neuro Oncol. 2014;16(3):372-381.
Diaz R, Guduk M, Romagnuolo R, et al. High-resolution whole-genome analysis of skull base chordomas implicates FHIT loss in chordoma pathogenesis. Neoplasia. 2012;14(9):788-798.
Le L, Nielsen G, Rosenberg A, et al. Recurrent chromosomal copy number alterations in sporadic chordomas. PLoS One. 2011;6(5):e18846.
Rinner B, Weinhaeusel A, Lohberger B, et al. Chordoma characterization of significant changes of the DNA methylation pattern. PLoS One. 2013;8(3):e56609.
Huang S, Zhang L, Sung Y, et al. Secondary EWSR1 gene abnormalities in SMARCB1-deficient tumors with 22q11-12 regional deletions: Potential pitfalls in interpreting EWSR1 FISH results. Genes Chromosomes Cancer. 2016;55(10):767-776.
Mobley B, McKenney J, Bangs C, et al. Loss of SMARCB1/INI1 expression in poorly differentiated chordomas. Acta Neuropathol. 2010;120(6):745-753.
Renard C, Pissaloux D, Decouvelaere A, Bourdeaut F, Ranchère D. Non-rhabdoid pediatric SMARCB1-deficient tumors: overlap between chordomas and malignant rhabdoid tumors? Cancer Genet. 2014;207(9):384-389.
Hasselblatt M, Thomas C, Hovestadt V, et al. Poorly differentiated chordoma with SMARCB1/INI1 loss: a distinct molecular entity with dismal prognosis. Acta Neuropathol. 2016;132(1):149-151.
Antonelli M, Raso A, Mascelli S, et al. SMARCB1/INI1 Involvement in Pediatric Chordoma: A Mutational and Immunohistochemical Analysis. Am J Surg Pathol. 2017;41(1):56-61.
Cha Y, Hong C, Kim D, Lee S, Park H, Kim S. Poorly differentiated chordoma with loss of SMARCB1/INI1 expression in pediatric patients: A report of two cases and review of the literature. Neuropathology. 2018;38(1):47-53.
Owosho A, Zhang L, Rosenblum M, Antonescu C. High sensitivity of FISH analysis in detecting homozygous SMARCB1 deletions in poorly differentiated chordoma: a clinicopathologic and molecular study of nine cases. Genes Chromosomes Cancer. 2018;57(2):89-95.
Rekhi B, Kosemehmetoglu K, Rane S, Soylemezoglu F, Bulut E. Poorly Differentiated Chordomas Showing Loss of INI1/SMARCB1: A Report of 2 Rare Cases With Diagnostic Implications. Int J Surg Pathol. 2018;26(7):637-643. doi:10.1177/1066896918768043
Yeter H, Kosemehmetoglu K, Soylemezoglu F. Poorly Differentiated Chordoma: Review of 53 Cases. APMIS. June 2019.
Shih A, Cote G, Chebib I, et al. Clinicopathologic characteristics of poorly differentiated chordoma. Mod Pathol. 2018;31(8):1237-1245.
Nachwalter R, Rothrock R, Katsoulakis E, et al. Treatment of dedifferentiated chordoma: a retrospective study from a large volume cancer center. J Neurooncol. July 2019.
Malgulwar P, Pathak P, Singh M, et al. Downregulation of SMARCB1/INI1 expression in pediatric chordomas correlates with upregulation of miR-671-5p and miR-193a-5p expressions. Brain Tumor Pathol. 2017;34(4):155-159.
Beccaria K, Tauziède-Espariat A, Monnien F, et al. Pediatric Chordomas: Results of a Multicentric Study of 40 Children and Proposal for a Histopathological Prognostic Grading System and New Therapeutic Strategies. J Neuropathol Exp Neurol. 2018;77(3):207-215.
Choy E, MacConaill L, Cote G, et al. Genotyping cancer-associated genes in chordoma identifies mutations in oncogenes and areas of chromosomal loss involving CDKN2A, PTEN, and SMARCB1. PLoS One. 2014;9(7):e101283.
Ribeiro MFSA, de Sousa MC, Hanna SA, et al. Tumor Reduction with Pazopanib in a Patient with Recurrent Lumbar Chordoma. Case Reports in Oncological Medicine. 2018;2018:1-7. doi:10.1155/2018/4290131
Tauziéde-Espariat A, Bresson D, Polivka M, et al. Prognostic and Therapeutic Markers in Chordomas: A Study  of 287 Tumors. J Neuropathol Exp Neurol. 2016;75(2):111-120.
Tirabosco R, Jacques T, Berisha F, Flanagan A. Assessment of integrase interactor 1 (INI-1) expression in primary tumours of bone. Histopathology. 2012;61(6):1245-1247.
Chavez J, Nasir U, Memon A, Perry A. Anaplastic chordoma with loss of INI1 and brachyury expression in a 2-year-old girl. Clin Neuropathol. 2014;33(6):418-420.
Li M, Zhai Y, Bai J, et al. SNF5 as a prognostic factor in skull base chordoma. J Neurooncol. 2018;137(1):139-146.
Miyahara H, Nodomi S, Umeda K, Itasaka S, Waki K, Imai T. Chemoradiotherapy for Unresectable INI1-negative Chordoma in a Child. J Pediatr Hematol Oncol. October 2018.
Chi S, Fouladi M, Shukla N, et al. Abstract A175: Phase 1 study of the EZH2 inhibitor, tazemetostat, in children with relapsed or refractory INI1-negative tumors including rhabdoid tumors, epithelioid sarcoma, chordoma, and synovial sarcoma. In: Epigenetic Targets. American Association for Cancer Research; 2018. doi:10.1158/1535-7163.targ-17-a175
Gounder M, Zhu G, Roshal L, et al. Immunologic Correlates of the Abscopal Effect in a SMARCB1/INI1-negative Poorly Differentiated Chordoma after EZH2 Inhibition and Radiotherapy. Clin Cancer Res. 2019;25(7):2064-2071.

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