INI1 is a ubiquitously expressed protein encoded by the hSNF/INI1 gene located on chromosome 22q.11.2. The hSNF/INI1 gene has been implicated as tumor suppressor gene in peripheral rhabdoid tumors and atypical teratoid/rhabdoid tumors (AT/RTs) of the central nervous system (CNS).

Homozygous inactivation of this gene is involved in the pathogenesis of renal and extrarenal malignant rhabdoid tumors of childhood, and immunohistochemical loss of INI1 was initially thought to be specific for this family of tumors.

Functions

Nucleosome remodeling complexes modify chromatin topology in an ATP-dependent manner by disrupting DNA-histone interactions. They thereby facilitating sliding of the nucleosome, and hence the accessibility of the DNA to transcription factors.

The SWI/SNF complex regulates genes locally, and analyses of yeast SWI/SNF mutants revealed that transcription of 5% of all yeast genes is influenced by SWI/SNF mutations.

The SWI/SNF core complex consists of SNF5/INI1, BRG1, BRM, BAF155, and BAF170. SWI/SNF interacts with many protein complexes central to cancer development, such as RB, p53, MYC, MLL, BRCA1, and beta-catenin; hence, functional inactivation of SWI/SNF impinges on a multitude of cellular growth control pathways.

Pathology

 somatic or germline deletions in

• malignant rhabdoid tumor
• atypical teratoid and rhabdoid tumor (AT/TR)
• brain primitive neuroectodermal tumor (cPNET)
• epithelioid sarcoma (19342946)

 germline mutations in

• malignant rhabdoid tumor syndrome (15101046)
• familial schwannomatosis (17357086)

Expression in tumors

 central nervous tumors (AT/TR apart) (nuclear pattern)

Diagnostic immunochemistry

 loss of INI1/SNF5 expression in tumors

• malignant rhabdoid tumors (MRT)
• atypical teratoid and rhabdoid tumor (AT/TR) (15105654)
• adult myoepithelial carcinoma
• myoepithelial carcinoma of soft tissue of the children (41%) (18043035)
• epithelioid sarcoma (90%) (19342946)
• epithelioid MPNSTs

 commercial antibodies

• monoclonal BAF47/SNF5 (INI1) antibody (clone 25, BD Transduction Labs, San Diego, CA)

Function

 modulation of cell growth and actin cytoskeleton organization (15150092)
 control of the G1-S transition of the cell cycle (12226744)

References

 Uterine neoplasms composed of rhabdoid cells do not exhibit loss of INI1 immunoreactivity and are not related to childhood malignant rhabdoid tumor. Al-Hussaini M, Hirschowitz L, McCluggage WG. Int J Gynecol Pathol. 2008 Apr;27(2):236-42. PMID: 18317218

 SMARCB1/INI1 protein expression in round cell soft tissue sarcomas associated with chromosomal translocations involving EWS: a special reference to SMARCB1/INI1 negative variant extraskeletal myxoid chondrosarcoma. Kohashi K, Oda Y, Yamamoto H, Tamiya S, Oshiro Y, Izumi T, Taguchi T, Tsuneyoshi M. Am J Surg Pathol. 2008 Aug;32(8):1168-74. PMID: 18580682

 Koitabashi M, Kanazawa T, Tamura K, Tsukada S, Suzuki M, Morikawa A, Ogawa C, Hirado J. A novel mutation of the SMARCB1 gene in a case of extrarenal malignant rhabdoid tumor. Cancer Genet Cytogenet. 2008 Feb;181(1):67-8. PMID: 18262058

 Hulsebos TJ, Plomp AS, Wolterman RA, Robanus-Maandag EC, Baas F, Wesseling P. Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am J Hum Genet. 2007 Apr;80(4):805-10. PMID: 17357086

 Rousseau-Merck MF, Fiette L, Klochendler-Yeivin A, Delattre O, Aurias A. Chromosome mechanisms and INI1 inactivation in human and mouse rhabdoid tumors. Cancer Genet Cytogenet. 2005 Mar;157(2):127-33. PMID: 15721633

 Roberts CW, Orkin SH. The SWI/SNF complex—chromatin and cancer. Nat Rev Cancer. 2004 Feb;4(2):133-42. PMID: 14964309

 Judkins AR, Mauger J, Ht A, Rorke LB, Biegel JA. Immunohistochemical Analysis of hSNF5/INI1 in Pediatric CNS Neoplasms. Am J Surg Pathol. 2004 May;28(5):644-650. PMID: 15105654

 Biegel JA, Kalpana G, Knudsen ES, Packer RJ, Roberts CW, Thiele CJ, Weissman B, Smith M. The role of INI1 and the SWI/SNF complex in the development of rhabdoid tumors: meeting summary from the workshop on childhood atypical teratoid/rhabdoid tumors. Cancer Res. 2002 Jan 1;62(1):323-8. PMID: 11782395

 Biegel JA, Tan L, Zhang F, et al. Alterations of the hSNF5/INI1 gene in central nervous system atypical teratoid/rhabdoid tumors and renal and extrarenal rhabdoid tumors. Clin Cancer Res. 2002;8:3461-3467.

 Biegel JA, Zhou JY, Rorke LB, et al. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 1999;59:74-79.

 Burger PC, Yu IT, Tihan T, et al. Atypical teratoid/rhabdoid tumor of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma: a Pediatric Oncology Group study. Am J Surg Pathol. 1998;22:1083-1092.

 Gessi M, Giangaspero F, Pietsch T. Atypical teratoid/rhabdoid tumors and choroid plexus tumors: when genetics surprise pathology. Brain Pathol. 2003;13:409-414.

 Hilden JM, Meerbaum S, Burger P, et al. Central nervous system atypical teratoid/rhabdoid tumor: results of therapy in children enrolled in a registry. J Clin Oncol. 2004;22:2877-2884.

 Hoot AC, Russo P, Judkins AR, et al. Immunohistochemical analysis of hSNF5/INI1 distinguishes renal and extra-renal malignant rhabdoid tumors from other pediatric soft tissue tumors. Am J Surg Pathol. 2004;28:1485-1491.

 Judkins AR, Burger PC, Hamilton RL, et al. INI1 protein expression distinguishes atypical teratoid/rhabdoid tumor from choroid plexus carcinoma. J Neuropathol Exp Neurol. 2005;64:391-397.

 Judkins AR, Mauger J, Ht A, et al. Immunohistochemical analysis of hSNF5/INI1 in pediatric CNS neoplasms. Am J Surg Pathol. 2004;28:644-650.

 Kalpana GV, Marmon S, Wang W, et al. Binding and stimulation of HIV-1 integrase by a human homolog of yeast transcription factor SNF5. Science. 1994;266:2002-2006.

 Kleihues P, Cavenee WK. World Health Organization Classification of Tumours Pathology & Genetics Tumours of the Nervous System. Lyon: IARC Press; 2000.

 Kraus JA, Oster C, Sorensen N, et al. Human medulloblastomas lack point mutations and homozygous deletions of the hSNF5/INI1 tumour suppressor gene. Neuropathol Appl Neurobiol. 2002;28:136-141.

 Packer RJ, Biegel JA, Blaney S, et al. Atypical teratoid/rhabdoid tumor of the central nervous system: report on workshop. J Pediatr Hematol Oncol. 2002;24:337-342.

 Perry A, Fuller CE, Judkins AR, et al. INI1 expression is retained in composite rhabdoid tumors, including rhabdoid meningiomas. Mod Pathol. 2005;18:951-958.

 Rorke LB, Biegel JA. Atypical teratoid/rhabdoid tumor. In: Kleihues P, Cavenee WK, eds. World Health Organization Classification of Tumours. Pathology & Genetics Tumours of the Nervous System. Lyon: IARC Press; 2000:145-148.

 Rorke LB, Packer RJ, Biegel JA. Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg. 1996;85:56-65.

 Rosty C, Peter M, Zucman J, et al. Cytogenetic and molecular analysis of a t(1;22)(p36;q11.2) in a rhabdoid tumor with a putative homozygous deletion of chromosome 22. Genes Chromosomes Cancer. 1998;21:82-89.

 Rousseau-Merck MF, Versteege I, Legrand I, et al. hSNF5/INI1 inactivation is mainly associated with homozygous deletions and mitotic recombinations in rhabdoid tumors. Cancer Res. 1999;59:3152-3156.

 Sevenet N, Lellouch-Tubiana A, Schofield D, et al. Spectrum of hSNF5/INI1 somatic mutations in human cancer and genotype-phenotype correlations. Hum Mol Genet. 1999;8:2359-2368.

 Stock C, Ambros IM, Lion T, et al. Detection of numerical and structural chromosome abnormalities in pediatric germ cell tumors by means of interphase cytogenetics. Genes Chromosomes Cancer. 1994;11:40-50.

 Tekautz TM, Fuller CE, Blaney S, et al. Atypical teratoid/rhabdoid tumors (ATRT): improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy. J Clin Oncol. 2005;23:1491-1499.

 Versteege I, Sevenet N, Lange J, et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature. 1998;394:203-206.