Human Genetics

, Volume 122, Issue 2, pp 117–127 | Cite as

High-density single nucleotide polymorphism array analysis in patients with germline deletions of 22q11.2 and malignant rhabdoid tumor

  • Eric M. Jackson
  • Tamim H. Shaikh
  • Sridharan Gururangan
  • Marilyn C. Jones
  • David Malkin
  • Sarah M. Nikkel
  • Craig W. Zuppan
  • Luanne M. Wainwright
  • Fan Zhang
  • Jaclyn A. Biegel
Original Investigation


Malignant rhabdoid tumors are highly aggressive neoplasms found primarily in infants and young children. The majority of rhabdoid tumors arise as a result of homozygous inactivating deletions or mutations of the INI1 gene located in chromosome band 22q11.2. Germline mutations of INI1 predispose to the development of rhabdoid tumors of the brain, kidney and extra-renal tissues, consistent with its function as a tumor suppressor gene. We now describe five patients with germline deletions in chromosome band 22q11.2 that included the INI1 gene locus, leading to the development of rhabdoid tumors. Two patients had phenotypic findings that were suggestive but not diagnostic for DiGeorge/Velocardiofacial syndrome (DGS/VCFS). The other three infants had highly aggressive disease with multiple tumors at the time of presentation. The extent of the deletions was determined by fluorescence in situ hybridization and high-density oligonucleotide based single nucleotide polymorphism arrays. The deletions in the two patients with features of DGS/VCFS were distal to the region typically deleted in patients with this genetic disorder. The three infants with multiple primary tumors had smaller but overlapping deletions, primarily involving INI1. The data suggest that the mechanisms underlying the deletions in these patients may be similar to those that lead to DGS/VCFS, as they also appear to be mediated by related, low copy repeats (LCRs) in 22q11.2. These are the first reported cases in which an association has been established between recurrent, interstitial deletions mediated by LCRs in 22q11.2 and a predisposition to cancer.



The authors thank Dr. Sulagna Saitta for her helpful and informative discussions. We would also like to acknowledge Dr. Eric Rappaport, Elizabeth Geiger and Madhavi Vaddi for their technical assistance. Supported by grants from the National Institutes of Health CA46274, CA98543 (J.A.B.) and GM64725 (T.H.S.). Eric Jackson receives grant support from the Neurosurgery Research and Education Foundation.

Supplementary material

439_2007_386_MOESM1_ESM.doc (24 kb)
Supplemental Table 1: Chromosomal positions of 22q11 LCRs (DOC 24.5 KB)
439_2007_386_MOESM2_ESM.doc (27 kb)
Supplemental Table 2: Deletion breakpoints in patients with germline 22q11.2 deletions (DOC 27 KB)


  1. Bailey JA, Gu Z, Clark RA, Reinert K, Samonte RV, Schwartz S, Adams MD, Myers EW, Li PW, Eichler EE (2002) Recent segmental duplications in the human genome. Science 297:1003–1007PubMedCrossRefGoogle Scholar
  2. Barbouti A, Stankiewicz P, Nusbaum C, Cuomo C, Cook A, Hoglund M, Johansson B, Hagemeijer A, Park SS, Mitelman F, Lupski JR, Fioretos T (2004) The breakpoint region of the most common isochromosome, i(17q), in human neoplasia is characterized by a complex genomic architecture with large, palindromic, low-copy repeats. Am J Hum Genet 74:1–10PubMedCrossRefGoogle Scholar
  3. Biegel JA (1999) Cytogenetics and molecular genetics of childhood brain tumors. Neuro-oncology 1:139–151PubMedCrossRefGoogle Scholar
  4. Biegel JA (2006) Molecular genetics of atypical teratoid/rhabdoid tumor. Neurosurg Focus 20:E11PubMedGoogle Scholar
  5. Biegel JA, Rorke LB, Packer RJ, Emanuel BS (1990) Monosomy 22 in rhabdoid or atypical tumors of the brain. J Neurosurg 73:710–714PubMedCrossRefGoogle Scholar
  6. Biegel JA, Zhou JY, Rorke LB, Stenstrom C, Wainwright LM, Fogelgren B (1999) Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res 59:74–79PubMedGoogle Scholar
  7. Biegel JA, Tan L, Zhang F, Wainwright L, Russo P, Rorke LB (2002) Alterations of the hSNF5/INI1 gene in central nervous system atypical teratoid/rhabdoid tumors and renal and extrarenal rhabdoid tumors. Clin Cancer Res 8:3461–3467PubMedGoogle Scholar
  8. Biggar SR, Crabtree GR (1999) Continuous and widespread roles for the Swi–Snf complex in transcription. EMBO J 18:2254–2264PubMedCrossRefGoogle Scholar
  9. Bignell GR, Huang J, Greshock J, Watt S, Butler A, West S, Grigorova M, Jones KW, Wei W, Stratton MR, Futreal PA, Weber B, Shapero MH, Wooster R (2004) High-resolution analysis of DNA copy number using oligonucleotide microarrays. Genome Res 14:287–295PubMedCrossRefGoogle Scholar
  10. Bourdeaut F, Freneaux P, Thuille B, Lellouch-Tubiana A, Nicolas A, Couturier J, Pierron G, Sainte-Rose C, Bergeron C, Bouvier R, Rialland X, Laurence V, Michon J, Sastre-Garau X, Delattre O (2007) hSNF5/INI1-deficient tumours and rhabdoid tumours are convergent but not fully overlapping entities. J Pathol 211:323–330PubMedCrossRefGoogle Scholar
  11. Conrad DF, Andrews TD, Carter NP, Hurles ME, Pritchard JK (2006) A high-resolution survey of deletion polymorphism in the human genome. Nat Genet 38:75–81PubMedCrossRefGoogle Scholar
  12. Cox C, Bignell G, Greenman C, Stabenau A, Warren W, Stephens P, Davies H, Watt S, Teague J, Edkins S, Birney E, Easton DF, Wooster R, Futreal PA, Stratton MR (2005) A survey of homozygous deletions in human cancer genomes. Proc Natl Acad Sci 102:4542–4547PubMedCrossRefGoogle Scholar
  13. Edelmann L, Pandita RK, Morrow BE (1999) Low-copy repeats mediate the common 3-Mb deletion in patients with velo-cardio-facial syndrome. Am J Hum Genet 64:1076–1086PubMedCrossRefGoogle Scholar
  14. Friedman JM, Baross A, Delaney AD, Ally A, Arbour L, Asano J, Bailey DK, Barber S, Birch P, Brown-John M, Cao M, Chan S, Charest DL, Farnoud N, Fernandes N, Flibotte S, Go A, Gibson WT, Holt RA, Jones SJ, Kennedy GC, Krzywinski M, Langlois S, Li HI, McGillivray BC, Nayar T, Pugh TJ, Rajcan-Separovic E, Schein JE, Schnerch A, Siddiqui A, Van Allen MI, Wilson G, Yong SL, Zahir F, Eydoux P, Marra MA (2006) Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation. Am J Hum Genet 79:500–513PubMedCrossRefGoogle Scholar
  15. Gibcus JH, Kok K, Menkema L, Hermsen MA, Mastik M, Kluin PM, van der Wal JE, Schuuring E (2007) High-resolution mapping identifies a commonly amplified 11q13.3 region containing multiple genes flanked by segmental duplications. Hum Genet 121:187–201PubMedCrossRefGoogle Scholar
  16. Hinds DA, Kloek AP, Jen M, Chen X, Frazer KA (2006) Common deletions and SNPs are in linkage disequilibrium in the human genome. Nat Genet 38:82–85PubMedCrossRefGoogle Scholar
  17. Janne PA, Li C, Zhao X, Girard L, Chen TH, Minna J, Christiani DC, Johnson BE, Meyerson M (2004) High-resolution single-nucleotide polymorphism array and clustering analysis of loss of heterozygosity in human lung cancer cell lines. Oncogene 23:2716–2726PubMedCrossRefGoogle Scholar
  18. Janson K, Nedzi LA, David O, Schorin M, Walsh JW, Bhattacharjee M, Pridjian G, Tan L, Judkins AR, Biegel JA (2005) Predisposition to atypical teratoid/rhabdoid tumor due to an inherited INI1 mutation. Pediatr Blood Cancer 47:279–284CrossRefGoogle Scholar
  19. Kusafuka T, Miao J, Yoneda A, Kuroda S, Fukuzawa M (2004) Novel germ-line deletion of SNF5/INI1/SMARCB1 gene in neonate presenting with congenital malignant rhabdoid tumor of kidney and brain primitive neuroectodermal tumor. Genes Chromosomes Cancer 40:133–139PubMedCrossRefGoogle Scholar
  20. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, Stange-Thomann N, Stojanovic N, Subramanian A, Wyman D, Rogers J, Sulston J, Ainscough R, Beck S, Bentley D, Burton J, Clee C, Carter N, Coulson A, Deadman R, Deloukas P, Dunham A, Dunham I, Durbin R, French L, Grafham D, Gregory S, Hubbard T, Humphray S, Hunt A, Jones M, Lloyd C, McMurray A, Matthews L, Mercer S, Milne S, Mullikin JC, Mungall A, Plumb R, Ross M, Shownkeen R, Sims S, Waterston RH, Wilson RK, Hillier LW, McPherson JD, Marra MA, Mardis ER, Fulton LA, Chinwalla AT, Pepin KH, Gish WR, Chissoe SL, Wendl MC, Delehaunty KD, Miner TL, Delehaunty A, Kramer JB, Cook LL, Fulton RS, Johnson DL, Minx PJ, Clifton SW, Hawkins T, Branscomb E, Predki P, Richardson P, Wenning S, Slezak T, Doggett N, Cheng JF, Olsen A, Lucas S, Elkin C, Uberbacher E, Frazier M et al (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921PubMedCrossRefGoogle Scholar
  21. Langdon JA, Lamont JM, Scott DK, Dyer S, Prebble E, Bown N, Grundy RG, Ellison DW, Clifford SC (2006) Combined genome-wide allelotyping and copy number analysis identify frequent genetic losses without copy number reduction in medulloblastoma. Genes Chromosomes Cancer 45:47–60PubMedCrossRefGoogle Scholar
  22. Maris JM, Hii G, Gelfand CA, Varde S, White PS, Rappaport E, Surrey S, Fortina P (2005) Region-specific detection of neuroblastoma loss of heterozygosity at multiple loci simultaneously using a SNP-based tag-array platform. Genome Res 15:1168–1176PubMedCrossRefGoogle Scholar
  23. McCarroll SA, Hadnott TN, Perry GH, Sabeti PC, Zody MC, Barrett JC, Dallaire S, Gabriel SB, Lee C, Daly MJ, Altshuler DM (2006) Common deletion polymorphisms in the human genome. Nat Genet 38:86–92PubMedCrossRefGoogle Scholar
  24. McDonald-McGinn DM, Reilly A, Wallgren-Pettersson C, Hoyme HE, Yang SP, Adam MP, Zackai EH, Sullivan KE (2006) Malignancy in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Am J Med Genet A 140:906–909PubMedGoogle Scholar
  25. McTaggart KE, Budarf ML, Driscoll DA, Emanuel BS, Ferreira P, McDermid HE (1998) Cat eye syndrome chromosome breakpoint clustering: identification of two intervals also associated with 22q11 deletion syndrome breakpoints. Cytogenet Cell Genet 81:222–228PubMedCrossRefGoogle Scholar
  26. Mendrzyk F, Korshunov A, Toedt G, Schwarz F, Korn B, Joos S, Hochhaus A, Schoch C, Lichter P, Radlwimmer B (2006) Isochromosome breakpoints on 17p in medulloblastoma are flanked by different classes of DNA sequence repeats. Genes Chromosomes Cancer 45:401–410PubMedCrossRefGoogle Scholar
  27. Ming JE, Geiger E, James AC, Ciprero KL, Nimmakayalu M, Zhang Y, Huang A, Vaddi M, Rappaport E, Zackai EH, Shaikh TH (2006) Rapid detection of submicroscopic chromosomal rearrangements in children with multiple congenital anomalies using high density oligonucleotide arrays. Hum Mutat 27:467–473PubMedCrossRefGoogle Scholar
  28. Muchardt C, Yaniv M (1999) The mammalian SWI/SNF complex and the control of cell growth. Sem Cell Dev Biol 10:189–195CrossRefGoogle Scholar
  29. Nannya Y, Sanada M, Nakazaki K, Hosoya N, Wang L, Hangaishi A, Kurokawa M, Chiba S, Bailey DK, Kennedy GC, Ogawa S (2005) A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays. Cancer Res 65:6071–6079PubMedCrossRefGoogle Scholar
  30. Raisanen J, Biegel JA, Hatanpaa KJ, Judkins A, White CL, Perry A (2005) Chromosome 22q deletions in atypical teratoid/rhabdoid tumors in adults. Brain Pathol 15:23–28PubMedCrossRefGoogle Scholar
  31. Rauch A, Pfeiffer RA, Leipold G, Singer H, Tigges M, Hofbeck M (1999) A novel 22q11.2 microdeletion in DiGeorge syndrome. Am J Hum Genet 64:659–666PubMedCrossRefGoogle Scholar
  32. Saitta SC, McGrath JM, Mensch H, Shaikh TH, Zackai EH, Emanuel BS (1999) A 22q11.2 deletion that excludes UFD1L and CDC45L in a patient with conotruncal and craniofacial defects. Am J Hum Genet 65:562–566PubMedCrossRefGoogle Scholar
  33. Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P, Maner S, Massa H, Walker M, Chi M, Navin N, Lucito R, Healy J, Hicks J, Ye K, Reiner A, Gilliam TC, Trask B, Patterson N, Zetterberg A, Wigler M (2004) Large-scale copy number polymorphism in the human genome. Science 305:525–528PubMedCrossRefGoogle Scholar
  34. Sevenet N, Sheridan E, Amram D, Schneider P, Handgretinger R, Delattre O (1999) Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am J Hum Genet 65:1342–1348PubMedCrossRefGoogle Scholar
  35. Shaikh TH, Kurahashi H, Saitta SC, O’Hare AM, Hu P, Roe BA, Driscoll DA, McDonald-McGinn DM, Zackai EH, Budarf ML, Emanuel BS (2000) Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum Mol Genet 9:489–501PubMedCrossRefGoogle Scholar
  36. Shaikh TH, O’Connor RJ, Pierpont ME, McGrath J, Hacker AM, Nimmakayalu M, Geiger E, Emanuel BS, Saitta SC (2007) Low copy repeats mediate distal chromosome 22q11.2 deletions: sequence analysis predicts breakpoint mechanisms. Genome Res 17:482–491PubMedCrossRefGoogle Scholar
  37. Sharp AJ, Locke DP, McGrath SD, Cheng Z, Bailey JA, Vallente RU, Pertz LM, Clark RA, Schwartz S, Segraves R, Oseroff VV, Albertson DG, Pinkel D, Eichler EE (2005) Segmental duplications and copy-number variation in the human genome. Am J Hum Genet 77:78–88PubMedCrossRefGoogle Scholar
  38. Shaw CJ, Lupski JR (2004) Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Hum Mol Genet 13(Spec No 1):R57–R64PubMedCrossRefGoogle Scholar
  39. Taylor MD, Gokgoz N, Andrulis IL, Mainprize TG, Drake JM, Rutka JT (2000) Familial posterior fossa brain tumors of infancy secondary to germline mutation of the hSNF5 gene. Am J Hum Genet 66:1403–1406PubMedCrossRefGoogle Scholar
  40. Tuzun E, Sharp AJ, Bailey JA, Kaul R, Morrison VA, Pertz LM, Haugen E, Hayden H, Albertson D, Pinkel D, Olson MV, Eichler EE (2005) Fine-scale structural variation of the human genome. Nat Genet 37:727–732PubMedCrossRefGoogle Scholar
  41. Versteege I, Sevenet N, Lange J, Rousseau-Merck MF, Ambros P, Handgretinger R, Aurias A, Delattre O (1998) Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394:203–206PubMedCrossRefGoogle Scholar
  42. Wieser R, Fritz B, Ullmann R, Muller I, Galhuber M, Storlazzi CT, Ramaswamy A, Christiansen H, Shimizu N, Rehder H (2005) Novel rearrangement of chromosome band 22q11.2 causing 22q11 microdeletion syndrome-like phenotype and rhabdoid tumor of the kidney. Hum Mutat 26:78–83PubMedCrossRefGoogle Scholar
  43. Zhao X, Li C, Paez JG, Chin K, Janne PA, Chen TH, Girard L, Minna J, Christiani D, Leo C, Gray JW, Sellers WR, Meyerson M (2004) An integrated view of copy number and allelic alterations in the cancer genome using single nucleotide polymorphism arrays. Cancer Res 64:3060–3071PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Eric M. Jackson
    • 1
  • Tamim H. Shaikh
    • 2
    • 3
  • Sridharan Gururangan
    • 4
  • Marilyn C. Jones
    • 5
  • David Malkin
    • 6
  • Sarah M. Nikkel
    • 7
  • Craig W. Zuppan
    • 8
  • Luanne M. Wainwright
    • 2
  • Fan Zhang
    • 2
  • Jaclyn A. Biegel
    • 2
    • 3
    • 9
  1. 1.Department of NeurosurgeryUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Division of Human Genetics and Molecular BiologyThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  3. 3.Department of PediatricsUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  4. 4.The Preston Robert Tisch Brain Tumor Center and the Departments of Pediatrics and SurgeryDuke University Medical CenterDurhamUSA
  5. 5.Division of Dysmorphology and GeneticsRady Children’s HospitalSan DiegoUSA
  6. 6.Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick ChildrenUniversity of TorontoTorontoCanada
  7. 7.Department of GeneticsChildren’s Hospital of Eastern OntarioOttawaCanada
  8. 8.Department of PathologyLoma Linda University Medical CenterLoma LindaUSA
  9. 9.The Children’s Hospital of Philadelphia, Abramson Research BuildingPhiladelphiaUSA

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