Rhabdoid Tumor : Role of SMARCB1 (INI1)
Section Editor: Dharam M. Ramnani, MD
Virginia Urology, Richmond, VA, USA
Image Description
Molecular Genetics: SMARCB1 protein makes up one core subunit of SWI/SNF chromatin-remodeling complex which plays a critical role in epigenetic regulation, cell cycle progression and crosstalk between signaling cascades. Two variants of the complex - BAF and PBAF are shown. The core subunits are shown in red. The differing subunits are colored yellow. Subunits coded by multigene families yielding slightly different amino acid sequences are shown blue.
Mechanisms of SMARCB1 inactivation in rhabdoid and related tumors include whole gene deletions, large intragenic deletions/duplications, insertions/deletions leading to a frameshift, splice-site mutations and nonsense mutations.
Rhabdoid Tumor Predisposition Syndrome: About one-third of patients with rhabdoid tumor carry germline mutations irrespective of the location of the tumor. The mutations involve SMARCB1 (type 1; 95% of cases) or SMARCA4 (type 2; 5% of cases). Germline SMARCB1 mutations are also responsible for approximately 45% of familial schwannomatosis. SMARCA4 is the primary ATPase in the SWI/SNF chromatin-remodeling complex. Small cell carcinoma of ovary, hypercalcemic type also harbors SMARCA4 mutations.
Detection of SMARCB1 or SMARCA4 mutations in rhabdoid tumor of kidney can be done by next generation sequencing. In addition, an INI1 immunohistochemistry assay has been developed in which loss of nuclear expression of the protein is seen in tumor cells. Preservation of INI1 staining in endothelial and inflammatory cells serves as an internal positive control. Loss of nuclear INI expression is not specific for rhabdoid tumor and is also seen in epithelioid sarcoma, cribriform neuroepithelial tumor, chordoma, and medullary renal cell carcinoma.
Image source: Kalimuthu SN, Chetty R. Gene of the month: SMARCB1. J Clin Pathol 2016; 69:484-489; used under Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license.
Mechanisms of SMARCB1 inactivation in rhabdoid and related tumors include whole gene deletions, large intragenic deletions/duplications, insertions/deletions leading to a frameshift, splice-site mutations and nonsense mutations.
Rhabdoid Tumor Predisposition Syndrome: About one-third of patients with rhabdoid tumor carry germline mutations irrespective of the location of the tumor. The mutations involve SMARCB1 (type 1; 95% of cases) or SMARCA4 (type 2; 5% of cases). Germline SMARCB1 mutations are also responsible for approximately 45% of familial schwannomatosis. SMARCA4 is the primary ATPase in the SWI/SNF chromatin-remodeling complex. Small cell carcinoma of ovary, hypercalcemic type also harbors SMARCA4 mutations.
Detection of SMARCB1 or SMARCA4 mutations in rhabdoid tumor of kidney can be done by next generation sequencing. In addition, an INI1 immunohistochemistry assay has been developed in which loss of nuclear expression of the protein is seen in tumor cells. Preservation of INI1 staining in endothelial and inflammatory cells serves as an internal positive control. Loss of nuclear INI expression is not specific for rhabdoid tumor and is also seen in epithelioid sarcoma, cribriform neuroepithelial tumor, chordoma, and medullary renal cell carcinoma.
Image source: Kalimuthu SN, Chetty R. Gene of the month: SMARCB1. J Clin Pathol 2016; 69:484-489; used under Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license.