Chordoma Foundation

SMARCB1/INI-1 and the SWI/SNF Complex

SMARCB1/INI-1 in Chordoma

SMARCB1 (also known as INI-1) 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 chordomas3 4 5 6 and deletion of the this locus specifically has been observed in poorly differentiated and pediatric chordomas2 7 8 9 10 11 12
  • No point mutations have been detected in any of the 9 SMARCB1/INI-1 exons.2 7 9
  • 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.13

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).14
  • Missense and nonsense mutations leading to loss of SMARCB1 protein expression were observed in 3 of 8 pediatric chordoma samples.14

Protein Expression

  • SMARCB1/INI-1 is normally expressed in all tissues (chordoma and non-chordoma).15 Absence of expression is rare in chordomas, but it has been observed occasionally.16
  • Loss of expression is more frequent in pediatric chordomas than in adult chordomas2, and loss of expression is also more frequent in poorly differentiated chordomas.7 8 9 11 17 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.

Clinical Evidence


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)18

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


Title


Locations


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

 

References

1.
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. [PubMed]
2.
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. [PubMed]
3.
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. [PubMed]
4.
Le L, Nielsen G, Rosenberg A, et al. Recurrent chromosomal copy number alterations in sporadic chordomas. PLoS One. 2011;6(5):e18846. [PubMed]
5.
Rinner B, Weinhaeusel A, Lohberger B, et al. Chordoma characterization of significant changes of the DNA methylation pattern. PLoS One. 2013;8(3):e56609. [PubMed]
6.
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. [PubMed]
7.
Mobley B, McKenney J, Bangs C, et al. Loss of SMARCB1/INI1 expression in poorly differentiated chordomas. Acta Neuropathol. 2010;120(6):745-753. [PubMed]
8.
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. [PubMed]
9.
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. [PubMed]
10.
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. [PubMed]
11.
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. August 2017. [PubMed]
12.
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. November 2017. [PubMed]
13.
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. [PubMed]
14.
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. [PubMed]
15.
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. [PubMed]
16.
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. [PubMed]
17.
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. [PubMed]