In the past few years high throughput methods for assessment of DNA copy number alterations have witnessed rapid progress. Both ‘in house’ developed BAC, cDNA, oligonucleotide and commercial arrays are now available and widely applied in the study of the human genome, particularly in the context of disease. Cancer cells are known to exhibit DNA losses, gains and amplifications affecting tumor suppressor genes and proto-oncogenes. Moreover, these patterns of genomic imbalances may be associated with particular tumor types or subtypes and may have prognostic value. Here we summarize recent array CGH findings in neuroblastoma, a pediatric tumor of the sympathetic nervous system. A total of 176 primary tumors and 53 cell lines have been analyzed on different platforms. Through these studies the genomic content and boundaries of deletions, gains and amplifications were characterized with unprecedented accuracy. Furthermore, in conjunction with cytogenetic findings, array CGH allows the mapping of breakpoints of unbalanced translocations at a very high resolution.

Alitalo K, Schwab M, Lin CC, Varmus HE, Bishop JM: Homogeneously staining chromosomal regions contain amplified copies of an abundantly expressed cellular oncogene (c-myc) in malignant neuroendocrine cells from a human colon carcinoma. Proc Natl Acad Sci USA 80:1707–1711 (1983).
Altura RA, Maris JM, Li H, Boyett JM, Brodeur GM, Look AT: Novel regions of chromosomal loss in familial neuroblastoma by comparative genomic hybridization. Genes Chromosomes Cancer 19:176–184 (1997).
Bader SA, Fasching C, Brodeur GM, Stanbridge EJ: Dissociation of suppression of tumorigenicity and differentiation in vitro effected by transfer of single human chromosomes into human neuroblastoma cells. Cell Growth Differ 2:245–255 (1991).
Beheshti B, Braude I, Marrano P, Thorner P, Zielenska M, Squire JA: Chromosomal localization of DNA amplifications in neuroblastoma tumors using cDNA microarray comparative genomic hybridization. Neoplasia 5:53–62 (2003).
Bignell GR, Huang J, Greshock J, Watt S, Butler A, et al: High-resolution analysis of DNA copy number using oligonucleotide microarrays. Genome Res 14:287–295 (2004).
Boon K, Caron HN, van Asperen R, Valentijn L, Hermus MC, et al: N-myc enhances the expression of a large set of genes functioning in ribosome biogenesis and protein synthesis. EMBO J 20:1383–1393 (2001).
Bown N: Neuroblastoma tumour genetics: clinical and biological aspects. J Clin Pathol 54:897–910 (2001).
Bown N, Cotterill S, Lastowska M, O’Neill S, Pearson AD, et al: Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. N Engl J Med 340:1954–1961 (1999).
Breen CJ, O’Meara A, McDermott M, Mullarkey M, Stallings RL: Coordinate deletion of chromosome 3p and 11q in neuroblastoma detected by comparative genomic hybridization. Cancer Genet Cytogenet 120:44–49 (2000).
Brinkschmidt C, Christiansen H, Terpe HJ, Simon R, Boecker W, et al: Comparative genomic hybridization (CGH) analysis of neuroblastomas – an important methodological approach in paediatric tumour pathology. J Pathol 181:394–400 (1997).
Brinkschmidt C, Poremba C, Christiansen H, Simon R, Schafer KL, et al: Comparative genomic hybridization and telomerase activity analysis identify two biologically different groups of 4s neuroblastomas. Br J Cancer 77:2223–2229 (1998).
Brodeur GM: Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 3:203–216 (2003).
Brodeur GM, Fong CT: Molecular biology and genetics of human neuroblastoma. Cancer Genet Cytogenet 41:153–174 (1989).
Brodeur GM, Sekhon G, Goldstein MN: Chromosomal aberrations in human neuroblastomas. Cancer 40:2256–2263 (1977).
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).
Cai WW, Mao JH, Chow CW, Damani S, Balmain A, Bradley A: Genome-wide detection of chromosomal imbalances in tumors using BAC microarrays. Nat Biotechnol 20:393–396 (2002).
Chen QR, Bilke S, Wei JS, Whiteford CC, Cenacchi N, et al: cDNA array-CGH profiling identifies genomic alterations specific to stage and MYCN-amplification in neuroblastoma. BMC Genomics 5:70 (2004).
Corvi R, Savelyeva L, Breit S, Wenzel A, Handgretinger R, et al: Non-syntenic amplification of MDM2 and MYCN in human neuroblastoma. Oncogene 10:1081–1086 (1995).
Cunsolo CL, Bicocchi MP, Petti AR, Tonini GP: Numerical and structural aberrations in advanced neuroblastoma tumours by CGH analysis; survival correlates with chromosome 17 status. Br J Cancer 83:1295–1300 (2000).
De Preter K, Pattyn F, Berx G, Strumane K, Menten B, et al: Combined subtractive cDNA cloning and array CGH: an efficient approach for identification of overexpressed genes in DNA amplicons. BMC Genomics 5:11 (2004).
De Preter K, Vandesompele J, Menten B, Carr P, Fiegler H, et al: Positional and functional mapping of a neuroblastoma differentiation gene on chromosome 11. BMC Genomics 6:11 (2005).
du Manoir S, Speicher MR, Joos S, Schrock E, Popp S, et al: Detection of complete and partial chromosome gains and losses by comparative genomic in situ hybridization. Hum Genet 90:590–610 (1993).
Ejeskar K, Aburatani H, Abrahamsson J, Kogner P, Martinsson T: Loss of heterozygosity of 3p markers in neuroblastoma tumours implicate a tumour-suppressor locus distal to the FHIT gene. Br J Cancer 77:1787–1791 (1998).
Fiegler H, Carr P, Douglas EJ, Burford DC, Hunt S, et al: DNA microarrays for comparative genomic hybridization based on DOP-PCR amplification of BAC and PAC clones. Genes Chromosomes Cancer 36:361–374 (2003).
Fitzgibbon J, Smith LL, Raghavan M, Smith ML, Debernardi S, et al: Association between acquired uniparental disomy and homozygous gene mutation in acute myeloid leukemias. Cancer Res 65:9152–9154 (2005).
Fix A, Peter M, Pierron G, Aurias A, Delattre O, Janoueix-Lerosey I: High-resolution mapping of amplicons of the short arm of chromosome 1 in two neuroblastoma tumors by microarray-based comparative genomic hybridization. Genes Chromosomes Cancer 40:266–270 (2004).
Garnis C, Baldwin C, Zhang L, Rosin MP, Lam WL: Use of complete coverage array comparative genomic hybridization to define copy number alterations on chromosome 3p in oral squamous cell carcinomas. Cancer Res 63:8582–8585 (2003).
Gilbert F, Feder M, Balaban G, Brangman D, Lurie DK, et al: Human neuroblastomas and abnormalities of chromosomes 1 and 17. Cancer Res 44:5444–5449 (1984).
Greshock J, Naylor TL, Margolin A, Diskin S, Cleaver SH, et al: 1-Mb resolution array-based comparative genomic hybridization using a BAC clone set optimized for cancer gene analysis. Genome Res 14:179–187 (2004).
Guo C, White PS, Weiss MJ, Hogarty MD, Thompson PM, et al: Allelic deletion at 11q23 is common in MYCN single copy neuroblastomas. Oncogene 18:4948–4957 (1999).
Hallstensson K, Thulin S, Aburatani H, Hippo Y, Martinsson T: Representational difference analysis and loss of heterozygosity studies detect 3p deletions in neuroblastoma. Eur J Cancer 33:1966–1970 (1997).
Heiskanen MA, Bittner ML, Chen Y, Khan J, Adler KE, et al: Detection of gene amplification by genomic hybridization to cDNA microarrays. Cancer Res 60:799–802 (2000).
Hirai M, Yoshida S, Kashiwagi H, Kawamura T, Ishikawa T, et al: 1q23 gain is associated with progressive neuroblastoma resistant to aggressive treatment. Genes Chromosomes Cancer 25:261–269 (1999).
Hoebeeck J, Michels E, Menten B, Van Roy N, Eggert A, et al: High resolution deletion breakpoint mapping using tiling-path BAC arrays defines two small distinct critical regions at 3p21–p22 in neuroblastoma. Int J Cancer in press (2006).
Hoshi M, Otagiri N, Shiwaku HO, Asakawa S, Shimizu N: Detailed deletion mapping of chromosome band 14q32 in human neuroblastoma defines a 1.1-Mb region of common allelic loss. Br J Cancer 82:1801–1807 (2000a).
Hoshi M, Shiwaku HO, Hayashi Y, Kaneko Y, Horii A: Deletion mapping of 14q32 in human neuroblastoma defines an 1,100-kb region of common allelic loss. Med Pediatr Oncol 35:522–525 (2000b).
Iehara T, Hamazaki M, Sawada T: Cytogenetic analysis of infantile neuroblastomas by comparative genomic hybridization. Cancer Lett 178:83–89 (2002).
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).
Jones TA, Flomen RH, Senger G, Nizetic D, Sheer D: The homeobox gene MEIS1 is amplified in IMR-32 and highly expressed in other neuroblastoma cell lines. Eur J Cancer 36:2368–2374 (2000).
Kallioniemi A, Kallioniemi OP, Sudar D, Rutovitz D, Gray JW, et al: Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258:818–821 (1992).
Kaneko Y, Kanda N, Maseki N, Sakurai M, Tsuchida Y, et al: Different karyotypic patterns in early and advanced stage neuroblastomas. Cancer Res 47:311–318 (1987).
Kuroda H, White PS, Sulman EP, Manohar CF, Reiter JL, et al: Physical mapping of the DDX1 gene to 340 kb 5′ of MYCN. Oncogene 13:1561–1565 (1996).
Lastowska M, Nacheva E, McGuckin A, Curtis A, Grace C, et al: Comparative genomic hybridization study of primary neuroblastoma tumors. United Kingdom Children’s Cancer Study Group. Genes Chromosomes Cancer 18:162–169 (1997).
Look AT, Hayes FA, Nitschke R, McWilliams NB, Green AA: Cellular DNA content as a predictor of response to chemotherapy in infants with unresectable neuroblastoma. N Engl J Med 311:231–235 (1984).
Lucito R, Healy J, Alexander J, Reiner A, Esposito D, et al: Representational oligonucleotide microarray analysis: a high-resolution method to detect genome copy number variation. Genome Res 13:2291–2305 (2003).
Manohar CF, Salwen HR, Brodeur GM, Cohn SL: Co-amplification and concomitant high levels of expression of a DEAD box gene with MYCN in human neuroblastoma. Genes Chromosomes Cancer 14:196–203 (1995).
Maris JM, Matthay KK: Molecular biology of neuroblastoma. J Clin Oncol 17:2264–2279 (1999).
Maris JM, Weiss MJ, Guo C, Gerbing RB, Stram DO, et al: Loss of heterozygosity at 1p36 independently predicts for disease progression but not decreased overall survival probability in neuroblastoma patients: a Children’s Cancer Group study. J Clin Oncol 18:1888–1899 (2000).
Molenaar JJ, van Sluis P, Boon K, Versteeg R, Caron HN: Rearrangements and increased expression of cyclin D1 (CCND1) in neuroblastoma. Genes Chromosomes Cancer 36:242–249 (2003).
Mosse Y, Greshock J, King A, Khazi D, Weber BL, Maris JM: Identification and high-resolution mapping of a constitutional 11q deletion in an infant with multifocal neuroblastoma. Lancet Oncol 4:769–771 (2003).
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).
Plantaz D, Mohapatra G, Matthay KK, Pellarin M, Seeger RC, Feuerstein BG: Gain of chromosome 17 is the most frequent abnormality detected in neuroblastoma by comparative genomic hybridization. Am J Pathol 150:81–89 (1997).
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).
Raghavan M, Lillington DM, Skoulakis S, Debernardi S, Chaplin T, et al: Genome-wide single nucleotide polymorphism analysis reveals frequent partial uniparental disomy due to somatic recombination in acute myeloid leukemias. Cancer Res 65:375–378 (2005).
Reiter JL, Brodeur GM: High-resolution mapping of a 130-kb core region of the MYCN amplicon in neuroblastomas. Genomics 32:97–103 (1996).
Reiter JL, Brodeur GM: MYCN is the only highly expressed gene from the core amplified domain in human neuroblastomas. Genes Chromosomes Cancer 23:134–140 (1998).
Savelyeva L, Corvi R, Schwab M: Translocation involving 1p and 17q is a recurrent genetic alteration of human neuroblastoma cells. Am J Hum Genet 55:334–340 (1994).
Scaruffi P, Parodi S, Mazzocco K, Defferrari R, Fontana V, et al: Detection of MYCN amplification and chromosome 1p36 loss in neuroblastoma by cDNA microarray comparative genomic hybridization. Mol Diagn 8:93–100 (2004).
Schleiermacher G, Janoueix-Lerosey I, Combaret V, Derre J, Couturier J, et al: Combined 24-color karyotyping and comparative genomic hybridization analysis indicates predominant rearrangements of early replicating chromosome regions in neuroblastoma. Cancer Genet Cytogenet 141:32–42 (2003).
Schwab M: Oncogene amplification in solid tumors. Semin Cancer Biol 9:319–325 (1999).
Schwab M, Alitalo K, Klempnauer KH, Varmus HE, Bishop JM, et al: Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour. Nature 305:245–248 (1983).
Seeger RC, Brodeur GM, Sather H, Dalton A, Siegel SE, et al: Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med 313:1111–1116 (1985).
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).
Shiloh Y, Shipley J, Brodeur GM, Bruns G, Korf B, et al: Differential amplification, assembly, and relocation of multiple DNA sequences in human neuroblastomas and neuroblastoma cell lines. Proc Natl Acad Sci USA 82:3761–3765 (1985).
Snijders AM, Nowak N, Segraves R, Blackwood S, Brown N, et al: Assembly of microarrays for genome-wide measurement of DNA copy number. Nat Genet 29:263–264 (2001).
Solinas-Toldo S, Lampel S, Stilgenbauer S, Nickolenko J, Benner A, et al: Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances. Genes Chromosomes Cancer 20:399–407 (1997).
Speicher MR, Gwyn Ballard S, Ward DC: Karyotyping human chromosomes by combinatorial multi-fluor FISH. Nat Genet 12:368–375 (1996).
Speleman F, Bown N: 17q gain in neuroblastoma, in Brodeur GM, Sawada T, Tsuchida Y, Voûte PA (eds): Neuroblastoma (Elsevier Science, Amsterdam, 2000).
Spieker N, van Sluis P, Beitsma M, Boon K, van Schaik BD, et al: The MEIS1 oncogene is highly expressed in neuroblastoma and amplified in cell line IMR32. Genomics 71:214–221 (2001).
Stallings RL, Nair P, Maris JM, Catchpoole D, McDermott M, et al: High-resolution analysis of chromosomal breakpoints and genomic instability identifies PTPRD as a canidate tumor supressor gene in neuroblastoma. Cancer Res 66:3673–3680 (2006).
Su WT, Alaminos M, Mora J, Cheung NK, La Quaglia MP, Gerald WL: Positional gene expression analysis identifies 12q overexpression and amplification in a subset of neuroblastomas. Cancer Genet Cytogenet 154:131–137 (2004).
Takita J, Hayashi Y, Kohno T, Shiseki M, Yamaguchi N, et al: Allelotype of neuroblastoma. Oncogene 11:1829–1834 (1995).
Theobald M, Christiansen H, Schmidt A, Melekian B, Wolkewitz N, et al: Sublocalization of putative tumor suppressor gene loci on chromosome arm 14q in neuroblastoma. Genes Chromosomes Cancer 26:40–46 (1999).
Thompson PM, Seifried BA, Kyemba SK, Jensen SJ, Guo C, et al: Loss of heterozygosity for chromosome 14q in neuroblastoma. Med Pediatr Oncol 36:28–31 (2001).
van Duin M, van Marion R, Watson JE, Paris PL, Lapuk A, et al: Construction and application of a full-coverage, high-resolution, human chromosome 8q genomic microarray for comparative genomic hybridization. Cytometry A 63:10–19 (2005).
Van Gele M, Van Roy N, Jauch A, Laureys G, Benoit Y, et al: Sensitive and reliable detection of genomic imbalances in human neuroblastomas using comparative genomic hybridisation analysis. Eur J Cancer 33:1979–1982 (1997).
Van Roy N, Laureys G, Cheng NC, Willem P, Opdenakker G, et al: 1;17 translocations and other chromosome 17 rearrangements in human primary neuroblastoma tumors and cell lines. Genes Chromosomes Cancer 10:103–114 (1994).
Van Roy N, Forus A, Myklebost O, Cheng NC, Versteeg R, Speleman F: Identification of two distinct chromosome 12-derived amplification units in neuroblastoma cell line NGP. Cancer Genet Cytogenet 82:151–154 (1995).
Van Roy N, Jauch A, Van Gele M, Laureys G, Versteeg R, et al: Comparative genomic hybridization analysis of human neuroblastomas: detection of distal 1p deletions and further molecular genetic characterization of neuroblastoma cell lines. Cancer Genet Cytogenet 97:139–142 (1997).
Van Roy N, Van Limbergen H, Vandesompele J, Van Gele M, Poppe B, et al: Combined M-FISH and CGH analysis allows comprehensive description of genetic alterations in neuroblastoma cell lines. Genes Chromosomes Cancer 32:126–135 (2001).
Van Roy N, Vandesompele J, Menten B, Nilsson H, De Smet E, et al: Translocation-excision-deletion-amplification mechanism leading to nonsyntenic coamplification of MYC and ATBF1. Genes Chromosomes Cancer 45:107–117 (2006).
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).
Vandesompele J, Speleman F, Van Roy N, Laureys G, Brinskchmidt C, et al: Multicentre analysis of patterns of DNA gains and losses in 204 neuroblastoma tumors: how many genetic subgroups are there? Med Pediatr Oncol 36:5–10 (2001).
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).
Vettenranta K, Aalto Y, Wikstrom S, Knuutila S, Saarinen-Pihkala U: Comparative genomic hybridization reveals changes in DNA-copy number in poor-risk neuroblastoma. Cancer Genet Cytogenet 125:125–130 (2001).
Wessendorf S, Fritz B, Wrobel G, Nessling M, Lampel S, et al: Automated screening for genomic imbalances using matrix-based comparative genomic hybridization. Lab Invest 82:47–60 (2002).
White PS, Thompson PM, Gotoh T, Okawa ER, Igarashi J, et al: Definition and characterization of a region of 1p36.3 consistently deleted in neuroblastoma. Oncogene 24:2684–2694 (2005).
Zhao X, Li C, Paez JG, Chin K, Janne PA, et al: An integrated view of copy number and allelic alterations in the cancer genome using single nucleotide polymorphism arrays. Cancer Res 64:3060–3071 (2004).
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