Journal of Neuro-Oncology

, Volume 73, Issue 2, pp 117–124 | Cite as

Cyclin D1 is overexpressed in atypical teratoid/rhabdoid tumor with hSNF5/INI1 gene inactivation

  • Hironori Fujisawa
  • Koichi Misaki
  • Yasushi Takabatake
  • Mitsuhiro Hasegawa
  • Junkoh Yamashita
Laboratory Investigation


Object: Although atypical teratoid/rhabdoid tumor (AT/RT) is known to generate through inactivation of the hSNF5/INI1 gene on chromosome 22q, the downstream molecular mechanism remains unclear. We histologically and molecularly reviewed our pediatric brain tumors for unrecognized AT/RTs and evaluated the role of cyclin D1, a potential molecular target of hSNF5/INI1. Methods: We analyzed 16 tumors under three years of age: seven medulloblastomas, three anaplastic ependymomas (E IIIs), two each of supratentorial primitive neuroectodermal tumors (sPNETs) and choroid plexus carcinomas (CPCs), and one each of neuroblastoma and pineoblastoma. Immunohistochemistry for glial fibrillary acidic protein, vimentin, epithelial membrane antigen, smooth muscle actin and cyclin D1 was performed. Polymerase chain reaction (PCR)-single-strand conformation polymorphism analysis with direct sequencing, differential PCR and microsatellite analysis were conducted for hSNF5/INI1mutation, homozygous deletion and loss of heterozygosity (LOH) on 22q, respectively. Because of the presence of rhabdoid cells and the polyimmunophenotypic features, the diagnosis was revised to AT/RT in five (31%) tumors, namely, two E IIIs and one each of medulloblastoma, CPC and pineoblastoma. Three of them harbored such hSNF5/INI1 aberrations as germline single base deletion (492/6 delC) and missense mutation (C157T) together with LOH 22q or homozygous deletion. Cyclin D1 was overexpressed in those three tumors but not in the two that lacked hSNF5/INI1 inactivation. Conclusion: AT/RT can be misdiagnosed as a variety of tumors, including ependymoma that potentially harbors LOH 22q. Our data indicate that cyclin D1 is a target of hSNF5/INI1in primary tumors.


atypical teratoid/rhabdoid tumor cyclin D1 overexpression hSNF5/INI1 gene 


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  1. 1.
    Rorke, LB, Packer, RJ, Biegel, JA. 1996Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entityJ Neurosurg855665PubMedGoogle Scholar
  2. 2.
    Burger, PC, Yu, IT, Tihan, T, Friedman, HS, Strother, DR, Kepner, JL, Duffner, P, Kun, LE, Perlman, EJ. 1998Atypical teratoid/rhabdoid tumor of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma: a Pediatric Oncology Group studyAm J Surg Pathol2210831092CrossRefPubMedGoogle Scholar
  3. 3.
    Biegel, JA, Fogelgren, B, Wainwright, LM, Zhou, JY, Bevan, H, Rorke, LB. 2000Germline INI1 mutation in a patient with a central nervous atypical teratoid tumor and renal rhabdoid tumorGenes Chromosomes Cancer283137CrossRefPubMedGoogle Scholar
  4. 4.
    Bonnin, JM, Rubinstein, LJ, Palmer, NF, Beckwith, JB. 1984The association of embryonal tumors originating in the kidney and in the brainA report of seven cases. Cancer5421372146Google Scholar
  5. 5.
    Fujisawa, H, Takabatake, Y, Fukusato, T, Tachibana, O, Tsuchiya, Y, Yamashita, J. 2003Molecular analysis of the rhabdoid predisposition syndrome in a child: a novel germline hSNF5/INI1 mutation and absence of c-myc amplificationJ Neuro-Oncol63257262CrossRefGoogle Scholar
  6. 6.
    Sévenet, N, Sheridan, E, Amram, D, Schneider, P, Handgreitinger, R, Delattre, O. 1999Constitutional mutations of the hSNF/INI1 gene predispose to a variety of cancerAm J Hum Genet6513421348CrossRefPubMedGoogle Scholar
  7. 7.
    Weeks, DA, Beckwith, JB, Mierau, GW, Luckey, DW. 1989Rhabdoid tumor of kidney. A report of 111 cases from the National Wilms’ Tumor Study Pathology Center.Am J Surg Pathol13439458PubMedGoogle Scholar
  8. 8.
    Parham, DM, Weeks, DA, Beckwith, JB. 1994The clinicopathologic spectrum of putative extrarenal rhabdoid tumors: an analysis of 42 cases studied with immunohistochemistry or electron microscopyAm J Surg Pathol1810101029PubMedGoogle Scholar
  9. 9.
    Utsuki, S, Kawano, N, Oka, H, Saegusa, H, Fujii, K, Yagishita, S, Scheithauer, BW. 1998[Atypical teratoid/rhabdoid tumor with ependymal differentiation: A case report]Jpn J Neurosurg7507512(in Japanese with English abstract)Google Scholar
  10. 10.
    Biegel, JA, Fogelgren, B, Zhou, JY, James, CD, Janss, AJ, Allen, JC, Zagzag, D, Raffel, C, Rorke, LB. 2000Mutations of the INI1 rhabdoid tumor suppressor gene in medulloblastomas and primitive neuroectodermal tumors of the central nervous systemClin Cancer Res627592763PubMedGoogle Scholar
  11. 11.
    Savla, J, Chen, TTY, Schneider, NR, Timmons, CF, Delattre, O, Tomlinson, GE. 2000Mutations of the hSNF5/INI1 gene in renal rhabdoid tumors with second primary brain tumorsJ Natl Cancer Inst92648650CrossRefPubMedGoogle Scholar
  12. 12.
    Biegel, JA, Zhou, JY, Rorke, LB, Stenstrom, C, Wainwright, LM, Fogelgren, B. 1999Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumorsCancer Res597479PubMedGoogle Scholar
  13. 13.
    Biegel, JA, Tan, L, Zhang, F, Wainwright, L, Russo, P, Rorke, LB. 2002Alterations of the hSNF5/INI1 gene in central nervous system atypical teratoid/rhabdoid tumors and renal and extrarenal rhabdoid tumorsClin Cancer Res834613467PubMedGoogle Scholar
  14. 14.
    Sévenet, N, Lellouch-Tubiana, A, Schofield, D, Hoang-Xuan, K, Gessler, M, Birnbaum, D, Jeanpierre, C, Jouvet, A, Delattre, O. 1999Spectrum of hSNF5/INI1 somatic mutations in human cancer and genotype-phenotype correlationsHum Mol Genet823592368CrossRefPubMedGoogle Scholar
  15. 15.
    Versteege, I, Sévenet, N, Lange, J, Rousseau-Merck, MF, Ambros, P, Handgretinger, R, Aurias, A, Delattre, O. 1998Truncating mutations of hSNF5/INI1 in aggressive paediatric cancerNature394203206CrossRefPubMedGoogle Scholar
  16. 16.
    Schnitzler, G, Sif, S, Kingston, RE. 1998Human SWI/SNF interconverts a nucleosome between its base state and a stable remodeled stateCell941727CrossRefPubMedGoogle Scholar
  17. 17.
    Zhang, F, Tan, L, Wainwrignt, LM, Bartolomei, MS, Biegel, JA. 2002No evidence for hypermethylation of the hSNF5/INI1 promoter in pediatric rhabdoid tumorsGenes Chromosomes Cancer34398405CrossRefPubMedGoogle Scholar
  18. 18.
    Sherr, CJ. 2000The Pezcoller lecture: cancer cell cycle revisitedCancer Res6036893695PubMedGoogle Scholar
  19. 19.
    Betz, BL, Strobeck, MW, Reisman, DN, Knudsen, ES, Weissman, BE. 2002Re-expression of hSNF5/INI1/BAF47 in pediatric tumor cells leads to G1 arrest associated with induction of p16ink4a and activation of RBOncogene2151935203CrossRefPubMedGoogle Scholar
  20. 20.
    Versteege, I, Medjkane, S, Rouillard, D, Delattre, O. 2002A key role of the hSNF5/INI1 tumor suppressor in the control of the G1-S transition of the cell cycleOncogene2164036412CrossRefPubMedGoogle Scholar
  21. 21.
    Zhang, ZK, Davies, KP, Allen, J, Zhu, L, Pestell, RG, Zagzag, D, Kalpana, GV. 2002Cell cycle arrest and repression of cyclin D1 transcription by INI1/hSNF5Mol Cell Biol2259755988CrossRefPubMedGoogle Scholar
  22. 22.
    Fujisawa, H, Marukawa, K, Hasegawa, M, Tohma, Y, Hayashi, Y, Uchiyama, N, Tachibana, O, Yamashita, J. 2002Genetic differences between neurocytoma and dysembryoplastic neuroepithelial tumor and oligodendroglial tumorsJ Neurosurg9713501355PubMedGoogle Scholar
  23. 23.
    Khoo, ML, Ezzat, S, Freeman, JL, Asa, SL. 2002Cyclin D1 protein expression predicts metastatic behavior in thyroid papillary microcarcinomas but is not associated with gene amplificationJ Clin Endocrinol Metab8718101813CrossRefPubMedGoogle Scholar
  24. 24.
    Misaki K, Marukawa K, Fujisawa H, Hayashi Y, Fukusato T, Minamoto T, Hasegawa M, Yamashita J. γ-Catenin expression correlates with good prognosis in medulloblastomas. J Neurosurg: Pediatrics (in press)Google Scholar
  25. 25.
    Kendal, R, Zhu, XL, Li, SQ, Rohan, T. 2001Cyclin D1 protein overexpression and gene amplification in benign breast tissue and breast cancer riskEur J Cancer Prev104351CrossRefPubMedGoogle Scholar
  26. 26.
    Watanabe, T, Hirota, Y, Arakawa, Y, Fujisawa, H, Tachibana, O, Hasegawa, M, Yamashita, J, Hayashi, Y. 2003Frequent LOH at chromosome 12q22–23 and apaf-1 inactivation in glioblastomaBrain Pathol13431439PubMedGoogle Scholar
  27. 27.
    Gilbert, J, Norris, MD, Haber, M, Kavallaris, M, Marshall, GM, Stewart, BW. 1993Determination of N-myc gene amplification in neuroblastoma by differential polymerase chain reactionMol Cell Probe7227234CrossRefGoogle Scholar
  28. 28.
    Kawate, S, Fukusato, T, Ohwada, S, Watanuki, A, Morishita, Y. 1999Amplification of c-myc in hepatocellular carcinoma: correlation with clinicopathologic features, proliferative activity and p53 overexpressionOncology57157163CrossRefPubMedGoogle Scholar
  29. 29.
    Eberhart, CG, Kratz, JE, Schuster, A, Goldthwaite, P, Cohen, KJ, Perlman, EJ, Burger, PC. 2002Comparative genomic hybridization detects an increased number of chromosomal alterations in large cell/anaplastic medulloblastomasBrain Pathol123644PubMedGoogle Scholar
  30. 30.
    Kleihues P, Cavenee WK, (eds): World Health Organiza- 640 tion classification of tumours: Pathology and genetics of 641 the nervous system. IARC Press, Lyon, 2000.Google Scholar
  31. 31.
    Giangaspero, F, Perilongo, G, Fondelli, MP, Brisigotti, M, Carollo, C, Burnelli, R, Burger, PC, Garre, ML. 1999Medulloblastoma with extensive nodularity: a variant with favorable prognosisJ Neurosurg91971977PubMedGoogle Scholar
  32. 32.
    Leonard, JR, Cai, DX, Rivet, DJ, Kaufman, BA, Park, TS, Levy, BK, Perry, A. 2001Large cell/anaplastic medulloblastomas and medullomyoblastomas: clinicopathological and genetic featuresJ Neurosurg958288PubMedGoogle Scholar
  33. 33.
    Cheng, SWG, Davies, KP, Yung, E, Beltran, RJ, Yu, J, Kalpana, GV. 1999c-MYC interacts with INI1/hSNF5 and requires the SWI/SNF complex for transactivation functionNat Genet22102105CrossRefPubMedGoogle Scholar
  34. 34.
    Ae, K, Kobayashi, N, Sakuma, R, Ogata, T, Kuroda, H, Kawaguchi, N, Shinomiya, K, Kitamura, Y. 2002Chromatin remodeling factor encoded by ini1 induces G1 arrest and apoptosis in ini1-deficient cellsOncogene2131123120CrossRefPubMedGoogle Scholar
  35. 35.
    Philipp, A, Schneider, A, Vasrik, I, Xiong, Y, Beach, D, Alitalo, K, Eilers, M. 1994Repression of cyclin D1: a novel function of MYCMol Cell Biol1440324043PubMedGoogle Scholar
  36. 36.
    Bruch, LA, Hill, DA, Cai, DX, Levy, BK, Dehner, LP, Perry, A. 2001A role for fluorescence in situ hybridization detection of chromosome 22q dosage in distinguishing atypical teratoid/rhabdoid tumors from medulloblastoma/central primitive neuroectodermal tumorsHum Pathol32156162Google Scholar
  37. 37.
    Kraus, JA, Oster, C, Sorensen, N, Berthold, F, Schlegel, U, Tonn, JC, Wiestler, OD, Pietsch, T. 2002Human medulloblastomas lack point mutations and homozygous deletions of the hSNF5/INI1 tumor suppressor geneNeuropathol Appl Neurobiol28136141CrossRefPubMedGoogle Scholar
  38. 38.
    Kraus, JA, Millas, W, Sorensen, N, Herbold, C, Schichor, C, Tonn, JC, Wiestler, OD, Deimling, A, Pietsch, T. 2001Indications for a tumor suppressor gene at 22q11 involved in the pathogenesis of ependymal tumors and distinct from hSNF5/INI1Acta Neuropathol (Berl)1026974Google Scholar
  39. 39.
    Weber, M, Stockhammer, F, Schmitz, U, Deimling, A. 2001Mutational analysis of INI1 in sporadic human brain tumorsActa Neuropathol (Berl)101479482Google Scholar
  40. 40.
    Wyatt-Ashmead, J, Kleinschmidt-DeMasters, B, Mierau, GW, Malkin, D, Orsini, E, McGavran, L, Foreman, NK. 2001Choroid plexus carcinomas and rhabdoid tumors: phenotypic and genotypic overlapPediat Develop Pathol4545549CrossRefGoogle Scholar
  41. 41.
    Gessi, M, Giangaspero, F, Pietsch, T. 2003Atypical teratoid/rhabdoid tumors and choroid plexus tumors: when genetics “surprise” pathologyBrain Pathol13409414PubMedGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Hironori Fujisawa
    • 1
  • Koichi Misaki
    • 1
  • Yasushi Takabatake
    • 2
  • Mitsuhiro Hasegawa
    • 1
  • Junkoh Yamashita
    • 1
  1. 1.Department of Neurosurgery, Division of Neuroscience, Graduate School of Medical ScienceKanazawa UniversityKanazawa, IshikawaJapan
  2. 2.Department of NeurosurgeryFukuiken Saiseikai HospitalFukuiJapan

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