Neuroblastoma is characterized by numerous recurrent large-scale chromosomal imbalances and gene amplifications which are associated with poor clinical outcome. The most common include MYCN amplification, loss of 1p, 3p and 11q, and gain of 17q genomic regions. Two of these abnormalities, MYCN amplification and loss of 11q, define different genetic subtypes of the disease with vastly different global gene expression profiles. The progress towards the identification of the genes and genetic pathways that have been affected by these abnormalities is reviewed and high resolution mapping of the chromosomal breakpoint regions using oligonucleotide array CGH (oaCGH) is discussed. oaCGH analysis is proving useful for both defining minimal regions of overlap of imbalances, as well as providing information on the molecular mechanisms that generate the chromosomal imbalances. These high resolution analyses have also permitted the detection of micro-deletions in the tumors that further assist in identifying genes important for neuroblastoma pathogenesis.

1.
Attiyeh EF, London WB, Mosse YP, Wang Q, Winter C, et al: Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med 353:2243–2253 (2005).
2.
Avet-Loiseau H, Venuat AM, Benard J, Leibovitch MP, Hartmann O, Bernheim A: Morphologic and molecular cytogenetics in neuroblastoma. Cancer 75:1694–1699 (1995).
3.
Barbouti A, Stankiewicz P, Nusbaum C, Cuomo C, Cook A, et al: 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 74:1–10 (2004).
4.
Barrett MT, Scheffer A, Ben-Dor A, Sampas N, Lipson D, et al: Comparative genomic hybridization using oligonucleotide microarrays and total genomic DNA. Proc Natl Acad Sci USA 101:17765–17770 (2004).
5.
Breen CJ, O’Meara A, McDermott M, Mullarkey M, Stallings RL: Co-ordinate deletion of chromosome 3p and 11q in neuroblastoma detected by comparative genomic hybridization. Cancer Genet Cytogenet 120:44–49 (2000).
6.
Brodeur GM: Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 3:203–216 (2003).
7.
Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM: Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 224:1121–1124 (1984).
8.
Chen QR, Bilke S, Wei JS, Whiteford CC, Cenacchi N: cDNA array-CGH profiling identifies genomic alterations specific to stage and MYCN- amplification in neuroblastoma. BMC Genomics 5:1–13 (2004).
9.
Elliott B, Richardson C, Jasin M: Chromosomal translocation mechanisms at intronic Alu elements in mammalian cells. Mol Cell 17:885–894 (2005).
10.
Esquela-Kerscher A, Slack FJ: Oncomirs – microRNAs with a role in cancer. Nature Rev Cancer 6:259–269 (2006).
11.
Guo C, White PS, Weiss MJ, Hogaerty MD, Thompson PM, et al: Allelic deletion at 11q23 is common in MYCN single copy neuroblastomas. Oncogene 18:4948–4957 (1999).
12.
Ishkanian AS, Malloff CA, Watson SK, DeLeeuw RJ, Chi B, et al: A tiling resolution DNA microarray with complete coverage of the human genome. Nat Genet 36:299–303 (2004).
13.
Kallioniemi A, Kallioniemi OP, Sudar D, Rutovitz D, Gray JW, et al: Comparative genomic hybridization: a rapid new method for detecting and mapping DNA amplification in tumors. Science 258:818–821 (1992).
14.
Knudson AG: Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820–823 (1971).
15.
Kolomietz E, Meyn MS, Pandita A, Squire JA: The role of Alu repeat clusters as mediators of recurrent chromosomal aberrations in tumors. Genes Chromosomes Cancer 35:97–112 (2002).
16.
Lastowska M, Cotterill S, Bown N, Cullinane C, Variend S, et al: Breakpoint position on 17q identifies the most aggressive neuroblastoma tumors. Genes Chromosomes Cancer 34:428–436 (2002).
17.
Luttikhuis M, Powell JE, Rees SA, Genus T, Chughtai S, et al: Neuroblastomas with chromosome 11q loss and single copy MYCN comprise a biologically distinct group of tumors with adverse prognosis. Brit J Cancer 85:531–537 (2001).
18.
McArdle L, McDermott M, Purcell R, Grehan D, O’Meara A, et al: DNA microarray analysis of gene expression in neuroblastoma displaying loss of 11q. Carcinogenesis 25:1599–1609 (2004).
19.
Mosse YP, Greshock J, Margolin A, Naylor T, Cole K, et al: High resolution detection and mapping of genomic DNA alterations in neuroblastoma. Genes Chromosomes Cancer 43:390–403 (2005).
20.
Plantaz D, Vandesompele J, Van Roy N, Lastowska M, Bown N, et al: Comparative genomic hybridization (CGH) analysis of stage 4 neuroblastoma reveals high frequency of 11q deletion in tumors lacking MYCN amplification. Int J Cancer 91:680–686 (2001).
21.
Pollack JR, Sorlie T, Perou CM, Rees CA, Jeffrey SS, et al: Microarray analysis reveals a major direct role of copy number alteration in the transcriptional program of human breast tumors. Proc Natl Acad Sci USA 99:12963–12968 (2002).
22.
Roix JJ, McQueen PG, Munson PJ, Parada LA, Misteli T: Spatial proximity of translocation-prone gene loci in human lymphomas. Nat Genet 34:287–291 (2003).
23.
Saglio G, Storlazzi CT, Giugliano E, Surace C, Anelli L, et al: A 76-kb duplicon maps close to the BCR gene on chromosome 22 and the ABL gene on chromosome 9: possible involvement in the genesis of the Philadelphia chromosome translocation. Proc Natl Acad Sci USA 99:9882–9887 (2002).
24.
Sato M, Takahashi K, Nagayama K, Arai Y, Ito N, et al: Identification of chromosome 9p as the most frequent target of homozygous deletions in lung cancer. Genes Chromosomes Cancer 44:405–414 (2005).
25.
Sebat J, Lakshmi B, Troge J, Alexander J, Young J, et al: Large-scale copy number polymorphism in the human genome. Science 305:525–528 (2004).
26.
Selzer RR, Richmond TA, Pofahl NJ, Green RD, Eis PS, et al: Analysis of chromosome breakpoints in neuroblastoma at sub-kilobase resolution using fine tiling oligonucleotide array CGH. Genes Chromosomes Cancer 44:305–319 (2005).
27.
Shaffer LG, Lupski JR: Molecular mechanisms for constitutional chromosomal rearrangements in humans. Annu Rev Genet 34:297–329 (2000).
28.
Spitz R, Hero B, Ernestus K, Berthold F: Deletions in chromosome arms 3p and 11q are new prognostic markers in localized and 4s neuroblastoma. Clin Can Res 9:52–58 (2003).
29.
Stallings RL, Carty P, McArdle L, Mullarkey M, McDermott M, et al: Molecular cytogenetic analysis of recurrent unbalanced t(11;17) in neuroblastoma. Cancer Genet Cytogenet 154:44–51 (2004).
30.
Stallings RL, Nair P, Maris JM, Catchpoole D, McDermot M, et al: High resolution analysis of chromosome breakpoints and genomic instability identifies PTPRD as a candidate tumor suppressor gene in neuroblastoma. Cancer Res 66:3673–3680 (2006).
31.
Stark B: der(11)t(11;17): a distinct cytogenetic pathway of advanced stage neuroblastoma (NBL) – detected by spectral karyotyping (SKY). Cancer Lett 197:75–79 (2003).
32.
Upender MB, Habermann JK, McShane LM, Korn EL, Barrett JC, et al: Chromosome transfer induced aneuploidy results in complex dysregulation of the cellular transcriptome in immortalized and cancer cells. Cancer Res 64:6941–6949 (2004).
33.
Valentijn LJ, Koppen A, van Asperen R, Root HA, Haneveld F, Versteeg R: Inhibition of a new differentiation pathway in neuroblastoma by copy number defects of N-myc<F00_Regular_Minion>,</F00_Regular_Minion> Cdc42<F00_Regular_Minion>,</F00_Regular_Minion> and nm23 genes. Cancer Res 65:3136–345 (2005).
34.
Vandesompele J, Van Roy N, Van Gele M, Laureys G, Ambros P, et al: Genetic heterogeneity of neuroblastoma studied by comparative genomic hybridization. Genes Chromosomes Cancer 23:141–152 (1998).
35.
Vandesompele J, Baudis M, De Preter K, Van Roy N, Ambros P, et al: Unequivocal delineation of clinicogenetic subgroups and development of a new model for improved outcome prediction in neuroblastoma. J Clin Oncol 23:2280–2299 (2005).
36.
Wang Q, Diskin S, Rappaport E, Attiyeh E, Mosse Y, et al: Integrative genomics identifies distinct molecular classes of neuroblastoma and shows that multiple genes are targeted by regional alterations in DNA copy number. Cancer Res 66:6050–6062 (2006).
37.
Wolf M, Mousses S, Hautaniemi S, Karhu R, Huusko P, et al: High-resolution analysis of gene copy number alterations in human prostate cancer using CGH on cDNA microarrays: impact of copy number on gene expression. Neoplasia 6:240–247 (2004).
38.
Woodings JA, Sharp SJ, Machesky LM: MIM-B, a putative metastasis suppressor protein, binds to actin and to protein tyrosine phosphatase δ. Biochem J 371:463–471 (2003).
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