Abstract
Cytogenetics has played a pivotal role in haematological malignancy, both as an aid to diagnosis and in identifying recurrent chromosomal rearrangements, an essential prerequisite to identifying genes involved in leukaemia and lymphoma pathogenesis. In the late 1980s, a series of technologies based around fluorescence in situ hybridisation (FISH) revolutionised the field. Interphase FISH, multiplex-FISH (M-FISH, SKY) and comparative genomic hybridisation (CGH) have emerged as the most significant of these. More recently, microarray technologies have come to prominence. In the acute leukaemias, the finding of characteristic gene expression signatures corresponding to biological subgroups has heralded gene expression profiling as a possible future alternative to current cytogenetic and morphological methods for diagnosis. In the lymphomas, high-resolution array CGH has successfully identified new regions of deletion and amplification, providing the prospect of disease-specific arrays.
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Albertson DG, Pinkel D (2003) Genomic microarrays in human genetic disease and cancer. Hum Mol Genet 12(Spec No 2):R145–R152
Ballerini P, Blaise A, Busson-Le Coniat M, Su XY, Zucman-Rossi J, Adam M, van den Akker J, Perot C, Pellegrino B, Landman-Parker J, Douay L, Berger R, Bernard OA (2002) HOX11L2 expression defines a clinical subtype of pediatric T-ALL associated with poor prognosis. Blood 100:991–997
Barber KE, Martineau M, Harewood L, Stewart M, Cameron E, Strefford JC, Rutherford S, Allen TD, Broadfield ZJ, Cheung KL, Harris RL, Jalali GR, Moorman AV, Robinson HM, Harrison CJ (2004) Amplification of the ABL gene in T-cell acute lymphoblastic leukemia. Leukemia 18:1153–1156
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 14:287–295
Brown J, Jawad M, Twigg SRF, Saracoglu K, Sauerbrey A, Thomas AE, Eils R, Harbott J, Kearney L (2002) A cryptic t(5;11)(q35;p15.5) in 2 children with acute myeloid leukemia and apparently normal karyotypes, identified by a multiplex fluorescence in situ hybridization telomere assay. Blood 99:2526–2531
Bullinger L, Dohner K, Bair E, Frohling S, Schlenk RF, Tibshirani R, Dohner H, Pollack JR (2004) Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med 350:1605–1616
Debernardi S, Lillington DM, Chaplin T, Tomlinson S, Amess J, Rohatiner A, Lister TA, Young BD (2003) Genome-wide analysis of acute myeloid leukemia with normal karyotype reveals a unique pattern of homeobox gene expression distinct from those with translocation-mediated fusion events. Genes Chromosomes Cancer 37:149–158
de Leeuw RJ, Davies JJ, Rosenwald A, Bebb G, Gascoyne RD, Dyer MJ, Staudt LM, Martinez-Climent JA, Lam WL (2004) Comprehensive whole genome array CGH profiling of mantle cell lymphoma model genomes. Hum Mol Genet 13(17):1827–1837
Döhner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, Döhner K, Bentz M, Lichter P (2000) Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910–1916
Elghezal H, Le Guyader G, Radford-Weiss I, Perot C, Van Den Akker J, Eydoux P, Vekemans M, Romana SP (2001) Reassessment of childhood B-lineage lymphoblastic leukemia karyotypes using spectral analysis. Genes Chromosomes Cancer 30:383–392
Fiegler H, Carr P, Douglas EJ, Burford DC, Hunt S, Scott CE, Smith J, Vetrie D, Gorman P, Tomlinson IP, Carter NP (2003) DNA microarrays for comparative genomic hybridization based on DOP-PCR amplification of BAC and PAC clones. Genes Chromosomes Cancer 36:361–374
Graux C, Cools J, Melotte C, Quentmeier H, Ferrando A, Levine R, Vermeesch JR, Stul M, Dutta B, Boeckx N, Bosly A, Heimann P, Uyttebroeck A, Mentens N, Somers R, MacLeod RA, Drexler HG, Look AT, Gilliland DG, Michaux L, Vandenberghe P, Wlodarska I, Marynen P, Hagemeijer A (2004) Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nat Genet 36:1084–1089
Greaves MF, Wiemels J (2003) Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 3:639–649
Greshock J, Naylor TL, Margolin A, Diskin S, Cleaver SH, Futreal PA, deJong PJ, Zhao S, Liebman M, Weber BL (2004) 1-Mb resolution array-based comparative genomic hybridization using a BAC clone set optimized for cancer gene analysis. Genome Res 14:179–187
Gruszka-Westwood AM, Horsley SW, Martinez-Ramirez A, Harrison CJ, Kempski H, Moorman AV, Ross FM, Griffiths M, Greaves MF, Kearney L (2004) Comparative expressed sequence hybridization studies of high-hyperdiploid childhood acute lymphoblastic leukaemia. Genes Chromosomes Cancer 41:191–202
Haas OA, Zeitlhofer P, Strehl S, Pfeilstoecker M, Koenig M, Weinhaeusel A (2004) A novel DNA/RNA FISH X inactivation assay reveals a nonrandom, ploidy-dependent acquisition of the active and inactive X chromosomes in childhood hyperdiploid acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL). Blood 104(11) suppl1, 307a
Haferlach T, Kohlman A, Schnittger S, Dugas M, Merk S, Hiddeman W, Kern W, Schoch C (2004) All clinically relevant leukemia subtypes can be diagnosed and classified based solely on gene expression profiling with an accuracy of 95.1%: a study on 1337 adult patients. Blood 104(11) suppl1, 44a
Harewood L, Robinson H, Harris R, Al-Obaidi MJ, Jalali GR, Martineau M, Moorman AV, Sumption N, Richards S, Mitchell C, Harrison CJ (2003) Amplification of AML1 on a duplicated chromosome 21 in acute lymphoblastic leukemia: a study of 20 cases. Leukemia 17:547–553
Harrison CJ (2001) Acute lymphoblastic leukaemia. Best Pract Res Clin Haematol 14:593–607
Harrison CJ, Martineau M, Secker-Walker LM (2001) The Leukaemia Research Fund/United Kingdom Cancer Cytogenetics Group Karyotype Database in acute lymphoblastic leukaemia: a valuable resource for patient management. Br J Haematol 113:3–10
Harrison CJ, Moorman AV, Barber KE, Broadfield ZJ, Cheung KL, Harris RL, Jalali GR, Robinson HM, Strefford JC, Stewart A, Wright S, Griffiths M, Ross FM, Harewood L, Martineau M (2005) Interphase molecular cytogenetic screening for chromosomal abnormalities of prognostic significance in childhood acute lymphoblastic leukaemia: a UK Cancer Cytogenetics Group Study. Br J Haemol 129:520–530
Helias C, Leymarie V, Entz-Werle N, Falkenrodt A, Eyer D, Costa JA, Cherif D, Lutz P, Lessard M (2002) Translocation t(5;14)(q35;q32) in three cases of childhood T cell acute lymphoblastic leukemia: a new recurring and cryptic abnormality. Leukemia 16:7–12
Hough RE, Goepel JR, Alcock HE, Hancock BW, Lorigan PC, Hammond DW (2001) Copy number gain at 12q12-14 may be important in the transformation from follicular lymphoma to diffuse large B cell lymphoma. Br J Cancer 84:499–503
Ishkanian AS, Malloff CA, Watson SK, DeLeeuw RJ, Chi B, Coe BP, Snijders A, Albertson DG, Pinkel D, Marra MA, Ling V, MacAulay C, Lam WL (2004) A tiling resolution DNA microarray with complete coverage of the human genome. Nat Genet 36:299–303
Jirtle RL (1999) Genomic imprinting and cancer. Exp Cell Res 248:18–24
Kallioniemi A, Kallioniemi OP, Sudar D et al (1992) Comparative genomic hybridization for molecular cytogenetic analysis of solid tumours. Science 258:818–821
Kohlhammer H, Schwaenen C, Wessendorf S, Holzmann K, Kestler HA, Kienle D, Barth TF, Moller P, Ott G, Kalla J, Radlwimmer B, Pscherer A, Stilgenbauer S, Dohner H, Lichter P, Bentz M (2004) Genomic DNA-chip hybridization in t(11;14)-positive mantle cell lymphomas shows a high frequency of aberrations and allows a refined characterization of consensus regions. Blood 104:795–801
Krzywinski M, Bosdet I, Smailus D, Chiu R, Mathewson C, Wye N, Barber S, Brown-John M, Chan S, Chand S, Cloutier A, Girn N, Lee D, Masson A, Mayo M, Olson T, Pandoh P, Prabhu AL, Schoenmakers E, Tsai M, Albertson D, Lam W, Choy CO, Osoegawa K, Zhao S, de Jong PJ, Schein J, Jones S, Marra MA (2004) A set of BAC clones spanning the human genome. Nucleic Acids Res 32:3651–3660
Langer S, Kraus J, Jentsch I, Speicher MR (2004) Multicolor chromosome painting in diagnostic and research applications. Chromosome Res 12:15–23
Larizza L, Magnani I, Beghini A (2005) The Kasumi-1 cell line: a t(8;21)-kit mutant model for acute myeloid leukemia. Leuk Lymphoma 46(2):247–255
Lichter P, Joos S, Bentz M, Lampel S (2000) Comparative genomic hybridization: uses and limitations. Semin Hematol 37:348–357
Lu YJ, Williamson D, Clark J, Wang R, Tiffin N, Skelton L, Gordon T, Williams R, Allan B, Jackman A, Cooper C, Pritchard-Jones K, Shipley J (2001) Comparative expressed sequence hybridization to chromosomes for tumor classification and identification of genomic regions of differential gene expression. Proc Natl Acad Sci U S A 98:9197–9202
Lu XY, Harris CP, Cooley L, Margolin J, Steuber PC, Sheldon M, Rao PH, Lau CC (2002) The utility of spectral karyotyping in the cytogenetic analysis of newly diagnosed pediatric acute lymphoblastic leukemia. Leukemia 16:2222–2227
Maia AT, van der Velden VH, Harrison CJ, Szczepanski T, Williams MD, Griffiths MJ, van Dongen JJ, Greaves MF (2003) Prenatal origin of hyperdiploid acute lymphoblastic leukemia in identical twins. Leukemia 17:2202–2206
Maia AT, Tussiwand R, Cazzaniga G, Rebulla P, Colman S, Biondi A, Greaves M (2004) Identification of preleukemic precursors of hyperdiploid acute lymphoblastic leukemia in cord blood. Genes Chromosomes Cancer 40:38–43
Martinez-Climent JA, Alizadeh AA, Segraves R, Blesa D, Rubio-Moscardo F, Albertson DG, Garcia-Conde J, Dyer MJ, Levy R, Pinkel D, Lossos IS (2003) Transformation of follicular lymphoma to diffuse large cell lymphoma is associated with a heterogeneous set of DNA copy number and gene expression alterations. Blood 101:3109–3117
Mathew S, Rao PH, Dalton J, Downing JR, Raimondi SC (2001) Multicolor spectral karyotyping identifies novel translocations in childhood acute lymphoblastic leukaemia. Leukemia 15:468–472
Matsuzaki H, Loi H, Dong S, Tsai YY, Fang J, Law J, Di X, Liu WM, Yang G, Liu G, Huang J, Kennedy GC, Ryder TB, Marcus GA, Walsh PS, Shriver MD, Puck JM, Jones KW, Mei R (2004) Parallel genotyping of over 10,000 SNPs using a one-primer assay on a high-density oligonucleotide array. Genome Res 14:414–425
Mohr B, Bornhauser M, Thiede C, Schakel U, Schaich M, Illmer T, Pascheberg U, Ehninger G (2000) Comparison of spectral karyotyping and conventional cytogenetics in 39 patients with acute myeloid leukemia and myelodysplastic syndrome. Leukemia 14:1031–1038
Moorman AV, Richards SM, Martineau M, Cheung KL, Robinson HM, Jalali GR, Broadfield ZJ, Harris RL, Taylor KE, Gibson BE, Hann IM, Hill FG, Kinsey SE, Eden TO, Mitchell CD, Harrison CJ, United Kingdom Medical Research Council's Childhood Leukemia Working Party (2003) Outcome heterogeneity in childhood high-hyperdiploid acute lymphoblastic leukemia. Blood 102:2756–2762
Mori H, Colman SM, Xiao Z, Ford AM, Healy LE, Donaldson C, Hows JM, Navarrete C, Greaves M (2000) Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc Natl Acad Sci U S A 99:8242–8247
Mrözek K, Heinonen K, Theil KS, Bloomfield CD (2002) Spectral karyotyping in patients with acute myeloid leukemia and a complex karyotype shows hidden aberrations, including recurrent overrepresentation of 21q, 11q, and 22q. Genes Chromosomes Cancer 34:137–153
Odera N, McCabe NR, Rubin CM (1992) Formation of a hyperdiploid karyotype in childhood acute lymphoblastic leukaemia. Blood 80:203–208
Panzer-Grumayer ER, Fasching K, Panzer S, Hettinger K, Schmitt K, Stockler-Ipsiroglu S, Haas OA (2002) Nondisjunction of chromosomes leading to hyperdiploid childhood B-cell precursor acute lymphoblastic leukemia is an early event during leukemogenesis. Blood 100:347–349
Paulsson K, Panagopoulos I, Knuutila S, Jee KJ, Garwicz S, Fioretos T, Mitelman F, Johansson B (2003) Formation of trisomies and their parental origin in hyperdiploid childhood acute lymphoblastic leukemia. Blood 102:3010–3015
Paulsson K, Morse H, Fioretos T, Behrendtz M, Strombeck B, Mitelman F, Johansson B (2004) Evidence for a single step mechanism in the origin of hyperdiploid childhood acute lymphoblastic leukemia. Blood 104(11) suppl1, 543a
Raghavan M, Lillington DM, Skoulakis S, Debernardi S, Chaplin T, Foot NJ, Lister TA, Young BD (2005) Genome-wide single nucleotide polymorphism analysis reveals frequent partial uniparental disomy due to somatic recombination in acute myeloid leukemias. Cancer Res 65:375–378
Robinson HM, Broadfield ZJ, Cheung KL, Harewood L, Harris RL, Jalali GR, Martineau M, Moorman AV, Taylor KE, Richards S, Mitchell C, Harrison CJ (2003) Amplification of AML1 in acute lymphoblastic leukemia is associated with a poor outcome. Leukemia 17:2249–2250
Ross ME, Zhou X, Song G, Shurtleff SA, Girtman K, Williams WK, Liu HC, Mahfouz R, Raimondi SC, Lenny N, Patel A, Downing JR (2003) Classification of pediatric acute lymphoblastic leukemia by gene expression profiling. Blood 102:2951–2959
Schoch C, Haferlach T, Bursch S, Gerstner D, Schnittger S, Dugas M, Kern W, Loffler W (2002) Loss of genetic material is more common than gain in acute myeloid leukemia with complex aberrant karyotype: a detailed analysis of 125 cases using conventional chromosome analysis and fluorescence in situ hybridization including 24-color FISH. Genes Chromosomes Cancer 35:20–29
Schröck E, du Manoir S, Veldman T et al (1996) Multicolor spectral karyotyping of human chromosomes. Science 273:494–497
Schwaenen C, Nessling M, Wessendorf S, Salvi T, Wrobel G, Radlwimmer B, Kestler HA, Haslinger C, Stilgenbauer S, Dohner H, Bentz M, Lichter P (2004) Automated array-based genomic profiling in chronic lymphocytic leukemia: development of a clinical tool and discovery of recurrent genomic alterations. Proc Natl Acad Sci U S A 101:1039–1044
Speicher MR, Ballard SG, Ward DC (1996) Karyotyping human chromosomes by combinatorial multi-fluor FISH. Nat Genet 12:368–375
Speleman F, Cauwelier B, Dastugue N, Cools J, Verhasselt B, Poppe B, Van Roy N, Vandesompele J, Graux C, Uyttebroeck A, Boogaerts M, De Moerloose B, Benoit Y, Selleslag D, Billiet J, Robert A, Huguet F, Vandenberghe P, De Paepe A, Marynen P, Hagemeijer A (2005) A new recurrent inversion, inv(7)(p15q34), leads to transcriptional activation of HOXA10 and HOXA11 in a subset of T-cell acute lymphoblastic leukemias. Leukemia 19:358–366
Strefford JC, van Delft F, Raghavan M, Robinson HM, Moorman AV, Young BD, Saha V, Harrison CJ (2004) Molecular characterization of AML1 (RUNX1) amplification: a poor risk chromosomal marker in acute lymphoblastic leukaemia (ALL). Blood 104(11) suppl1, 43a
Streubel B, Chott A, Huber D, Exner M, Jager U, Wagner O, Schwarzinger I (2004) Lymphoma-specific genetic aberrations in microvascular endothelial cells in B-cell lymphomas. N Engl J Med 351:250–259
Tanke HJ, Wiegant J, van Gijlswijk RPM, Bezrookove V, Pattenier H, Heetebrij RJ, Talman EG, Raap AK, Vrolijk J (1999) New strategy for multi-colour fluorescence in situ hybridisation: COBRA: combined binary ratio labelling. Eur J Hum Genet 7:2–11
Valk PJ, Verhaak RG, Beijen MA, Erpelinck CA, van Waalwijk van Doorn-Khosrovani B, Boer JM, Beverloo HB, Moorhouse MJ, van der Spek PJ, Lowenberg B, Delwel R (2004) Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 350(16):1617–1628
van der Burg M, Poulsen TS, Hunger SP, Beverloo HB, Smit EM, Vang-Nielsen K, Langerak AW, van Dongen JJ (2004) Split-signal FISH for detection of chromosome aberrations in acute lymphoblastic leukemia. Leukemia 18:895–908
van Limbergen H, Poppe B, Michaux L, Herens C, Brown J, Noens L, Berneman Z, De Bock R, De Paepe A, Speleman F (2002) Identification of cytogenetic subclasses and recurring chromosomal aberrations in AML and MDS with complex karyotypes using M-FISH. Genes Chromosomes Cancer 33:60–72
van Zutven LJ, Velthuizen SC, Wolvers-Tettero IL, van Dongen JJ, Poulsen TS, MacLeod RA, Beverloo HB, Langerak AW (2004) Two dual-color split signal fluorescence in situ hybridization assays to detect t(5;14) involving HOX11L2 or CSX in T-cell acute lymphoblastic leukemia. Haematologica 89(6):671–678
Viardot A, Martin-Subero JI, Siebert R, Harder S, Gesk S, Bentz M, Schlegelberger B (2001) Detection of secondary genetic aberrations in follicle center cell derived lymphomas: assessment of the reliability of comparative genomic hybridization and standard chromosome analysis. Leukemia 15:177–183
Walter MJ, Ries RE, Armstrong J, O'Gara B, Vardiman JW, Caliguiri MA, Bloomfield CD, Hodgson G, Gray JW, Wilson RK, Mardis ER, Ley TJ (2004) Genomic copy number alterations present in AML bone marrow samples with normal cytogenetics. Blood 104(11) suppl1, 44axx
Wessendorf S, Schwaenen C, Kohlhammer H, Kienle D, Wrobel G, Barth TF, Nessling M, Moller P, Dohner H, Lichter P, Bentz M (2003) Hidden gene amplifications in aggressive B-cell non-Hodgkin lymphomas detected by microarray-based comparative genomic hybridization. Oncogene 22:1425–1429
Yeoh EJ, Ross ME, Shurtleff SA, Williams WK, Patel D, Mahfouz R, Behm FG, Raimondi SC, Relling MV, Patel A, Cheng C, Campana D, Wilkins D, Zhou X, Li J, Liu H, Pui CH, Evans WE, Naeve C, Wong L, Downing JR (2002) Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 1:1133–1143
Zhang FF, Murata-Collins JL, Gaytan P, Forman SJ, Kopecky KJ, Willman CL, Appelbaum FR, Slovak ML (2000) Twenty-four-color spectral karyotyping reveals chromosome aberrations in cytogenetically normal acute myeloid leukemia. Genes Chromosomes Cancer 28:318–328
Acknowledgements
We wish to acknowledge the Medical Research Council UK and the Leukaemia Research Fund UK for financial support. We also thank Alan Mackay and the Breakthrough Breast Cancer microarray facility, Institute of Cancer Research for access to and advice on the use of the 1-Mbp BAC arrays.
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Communicated by D. Griffin
Review related to the 15th International Chromosome Conference (ICC XV), held in September 2004, Brunel University, London, UK
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Kearney, L., Horsley, S.W. Molecular cytogenetics in haematological malignancy: current technology and future prospects. Chromosoma 114, 286–294 (2005). https://doi.org/10.1007/s00412-005-0002-z
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DOI: https://doi.org/10.1007/s00412-005-0002-z