Abstract
Recently, DNA microarray technology has opened new avenues for the understanding of lymphomas. By hybridization of cDNA to arrays containing >10,000 different DNA fragments, this approach allows the simultaneous evaluation of the mRNA expression of thousands of genes in a single experiment. Using sophisticated bioinformatic tools, the huge amount of raw data can be clustered resulting in (1) tumor subclassification, (2) identification of pathogenetically relevant genes, or (3) biological predictors for the clinical course. This approach already has provided novel insights into different entities of B-cell non-Hodgkin's lymphomas. Genomic DNA chip hybridization (matrix-CGH) is a complementary approach focussing on genomic aberrations. In this review, we discuss the impact of this new technology both with regard to methodological aspects as well as to novel findings influencing our understanding of lymphomas.
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Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Staudt LM (2000) Distinct types of diffuse large B-cell lymphoma identified by expression profiling. Nature 403:503–511
Armstrong SA, Staunton JE, Silverman LB, Pieters R, den Boer ML, Minden MD, Sallan SE, Lander ES, Golub TR, Korsmeyer SJ (2002) MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet 30:41–47
Baldwin AS (2001) Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest 107:241–246
Brown MP, Grundy WN, Lin D, Cristianini N, Sugnet CW, Furey TS, Ares M Jr, Haussler D (2000) Knowledge-based analysis of microarray gene expression data by using support vector machines. Proc Natl Acad Sci U S A 97:262–267
Bruder CE, Hirvela C, Tapia-Paez I, Fransson I, Segraves R, Hamilton G, Zhang XX, Evans DG, Wallace AJ, Baser ME, Zucman-Rossi J, Hergersberg M, Boltshauser E, Papi L, Rouleau GA, Poptodorov G, Jordanova A, Rask-Andersen H, Kluwe L, Mautner V, Sainio M, Hung G, Mathiesen T, Moller C, Pulst SM, Harder H, Heiberg A, Honda M, Niimura M, Sahlen S, Blennow E, Albertson DG, Pinkel D, Dumanski JP (2001) High resolution deletion analysis of constitutional DNA from neurofibromatosis type 2 (NF2) patients using microarray-CGH. Hum Mol Genet 10:271–282
Carter NP, Fiegler H, Piper J (2002) Comparative analysis of comparative genomic hybridization microarray technologies: report of a workshop sponsored by the Wellcome Trust. Cytometry 49:43–48
Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, Lichtman SM, Schulman P, Vinciguerra VP, Rai KR, Ferrarini M, Chiorazzi N (1999) Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94:1840–1847
Davis RE, Brown KD, Siebenlist U, Staudt LM. (2001) Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med 194:1861–1874
DeRisi JL, Iyer VR, Brown PO (1997) Exploring the metabolic and genetic control of gene expression on a genomic scale. Science 278:680–686
Döhner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, Dohner K, Bentz M, Lichter P (2000) Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910–1916
Duggan DJ, Bittner M, Chen Y, Meltzer P, Trent JM (1999) Expression profiling using cDNA microarrays. Nat Genet 21 [Suppl 1]:10–14
Eisen MB, Spellman PT, Brown PO, Botstein D (1998) Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A 95:14863–14868
Federico M, Vitolo U, Zinzani PL, Chisesi T, Clo V, Bellesi G, Magagnoli M, Liberati M, Boccomini C, Niscola P, Pavone V, Cuneo A, Santini G, Brugiatelli M, Baldini L, Rigacci L, Resegotti L (2000) Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases. Intergruppo Italiano Linfomi. Blood 95:783–789
Fritz B, Schubert F, Wrobel G, Schwaenen C, Wessendorf S, Nessling M, Korz C, Rieker RJ, Montgomery K, Kucherlapati R, Mechtersheimer G, Eils R, Joos S, Lichter P (2002) Microarray-based copy number and expression profiling in dedifferentiated and pleomorphic liposarcoma. Cancer Res 62:2993–2998
Gress TM, Muller-Pillasch F, Geng M, Zimmerhackl F, Zehetner G, Friess H, Buchler M, Adler G, Lehrach H (1996) A pancreatic cancer-specific expression profile. Oncogene 13:1819–1830
Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK (1999) Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94:1848–1854
Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC (1994) A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 84:1361–1392
Huang JZ, Sanger WG, Greiner TC, Staudt LM, Weisenburger DD, Pickering DL, Lynch JC, Armitage JO, Warnke RA, Alizadeh AA, Lossos IS, Levy R, Chan WC (2002) The t(14;18) defines a unique subset of diffuse large B-cell lymphoma with a germinal center B-cell gene expression profile. Blood 99:2285–2290
Jaffe ES, Harris NL, Stein H, Vardiman JW (2001) World Health Organization classification of tumors. Pathology and genetics of tumors of the hematopoietic and lymphoid tissues. IARC Press, Lyon, France
Johansson B, Mertens F, Mitelman F (1995) Cytogenetic evolution patterns in non-Hodgkin's lymphoma. Blood 86:3905–3914
Keating MJ (1998) Chronic lymphocytic leukemia in the next decade: where do we go from here? Semin Hematol. 35 [Suppl 3]:27–33
Klein U, Tu Y, Stolovitzky GA, Mattioli M, Cattoretti G, Husson H, Freedman A, Inghirami G, Cro L, Baldini L, Neri A, Califano A, Dalla-Favera R (2001) Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med 194:1625–1638
Kröber A, Seiler T, Benner A, Bullinger L, Bruckle E, Lichter P, Döhner H, Stilgenbauer S (2002) V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 100:1410–1416
Küppers R, Klein U, Hansmann ML, Rajewsky K (1999) Cellular origin of human B-cell lymphomas. N Engl J Med 341:1520–1529
Lichter P, Joos S, Bentz M, Lampel S (2000) Comparative genomic hybridization: uses and limitations. Semin Hematol 37:348–357
Lipshutz RJ, Fodor SP, Gingeras TR, Lockhart DJ (1999) High density synthetic oligonucleotide arrays. Nat Genet 21 [Suppl 1]:20–24
Lockhart DJ, Dong H, Byrne MC, Follettie MT, Gallo MV, Chee MS, Mittmann M, Wang C, Kobayashi M, Horton H, Brown EL (1996) Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat Biotechnol 14:1675–1680
Lossos IS, Alizadeh AA, Diehn M, Warnke R, Thorstenson Y, Oefner PJ, Brown PO, Botstein D, Levy R (2002) Transformation of follicular lymphoma to diffuse large-cell lymphoma: alternative patterns with increased or decreased expression of c-myc and its regulated genes. Proc Natl Acad Sci U S A 99:8886–8891
Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, Reiffers J, Silver RT, Tura S, Fischer T, Deininger MW, Schiffer CA, Baccarani M, Gratwohl A, Hochhaus A, Hoelzer D, Fernandes-Reese S, Gathmann I, Capdeville R, O'Brien SG (2002) A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100:1965–1971
Pinkel D, Segraves R, Sudar D, Clark S, Poole I, Kowbel D, Collins C, Kuo WL, Chen C, Zhai Y, Dairkee SH, Ljung BM, Gray JW, Albertson DG (1998) High resolution analysis of DNA copy number variations using comparative genomic hybridization to microarrays. Nat Genet 20:207–211
Pollack JR, Perou CM, Alizadeh AA, Eisen MB, Pergamenschikov A, Williams CF, Jeffrey SS, Botstein D, Brown PO (1999) Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nat Genet 23:41–46
Pui CH, Evans WE (1998) Acute lymphoblastic leukemia. N Engl J Med 339:605–615
Rabbitts TH (1994) Chromosomal translocations in human cancer. Nature 372:143–149
Rosenwald A, Alizadeh AA, Widhopf G, Simon R, Davis RE, Yu X, Yang L, Pickeral OK, Rassenti LZ, Powell J, Botstein D, Byrd JC, Grever MR, Cheson BD, Chiorazzi N, Wilson WH, Kipps TJ, Brown PO, Staudt LM (2001) Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 194:1639–1647
Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, Gascoyne RD, Muller-Hermelink HK, Smeland EB, Giltnane JM, Hurt EM, Zhao H, Averett L, Yang L, Wilson WH, Jaffe ES, Simon R, Klausner RD, Powell J, Duffey PL, Longo DL, Greiner TC, Weisenburger DD, Sanger WG, Dave BJ, Lynch JC, Vose J, Armitage JO, Montserrat E, Lopez-Guillermo A, Grogan TM, Miller TP, LeBlanc M, Ott G, Kvaloy S, Delabie J, Holte H, Krajci P, Stokke T, Staudt LM (2002) The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346:1937–1947
Schena M, Shalon D, Davis RW, Brown PO (1995) Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270:467–470
Schlegelberger B, Zwingers T, Harder L, Nowotny H, Siebert R, Vesely M, Bartels H, Sonnen R, Hopfinger G, Nader A, Ott G, Muller-Hermelink K, Feller A, Heinz R (1999) Clinicopathogenetic significance of chromosomal abnormalities in patients with blastic peripheral B-cell lymphoma. Kiel-Wien-Lymphoma Study Group. Blood 94:3114–3120
Schwaenen C, Nessling M, Wessendorf S, Göttel D, Wrobel G, Döhner H, Bentz M, Stilgenbauer S, Lichter P (2002) Automated genomic profiling for recurrent chromosomal aberrations in B-CLL using microarray based comparative genomic hybridization (Matrix-CGH). Ann Oncol 13 [Suppl 2]:004
Shipp MA, Abeloff MD, Antman KH, Carroll G, Hagenbeek A, Loeffler M, Montserrat E, Radford JA, Salles G, Schmitz N, Symann M, Armitage JO, Philip T, Coiffier B (1999) International Consensus Conference on High-Dose Therapy with Hematopoietic Stem Cell Transplantation in Aggressive Non-Hodgkin's Lymphomas: report of the jury. J Clin Oncol 17:423–429
Shipp MA, Ross KN, Tamayo P, Weng AP, Kutok JL, Aguiar RC, Gaasenbeek M, Angelo M, Reich M, Pinkus GS, Ray TS, Koval MA, Last KW, Norton A, Lister TA, Mesirov J, Neuberg DS, Lander ES, Aster JC, Golub TR (2002) Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med 8:68–74
Snijders AM, Nowak N, Segraves R, Blackwood S, Brown N, Conroy J, Hamilton G, Hindle AK, Huey B, Kimura K, Law S, Myambo K, Palmer J, Ylstra B, Yue JP, Gray JW, Jain AN, Pinkel D, Albertson DG (2001) Assembly of microarrays for genome-wide measurement of DNA copy number. Nat Genet 29:263–264
Solinas-Toldo S, Lampel S, Stilgenbauer S, Nickolenko J, Benner A, Döhner H, Cremer T, Lichter P (1997) Matrix-based comparative genomic hybridization: biochips to screen for genomic inbalances. Genes Chromosomes Cancer 20:399–407
Staudt LM (2002) Gene expression profiling of lymphoid malignancies. Annu Rev Med 53:303–318
The International Non-Hodgkin's Lymphoma Prognostic Factors Project (1993) A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 329:987–994
Veltman JA, Schoenmakers EF, Eussen BH, Janssen I, Merkx G, van Cleef B, van Ravenswaaij CM, Brunner HG, Smeets D, van Kessel AG (2002) High-throughput analysis of subtelomeric chromosome rearrangements by use of array-based comparative genomic hybridization. Am J Hum Genet 70:1269–1276
Viardot A, Möller P, Högel J, Werner K, Mechtersheimer G, Ho AD, Ott G, Barth TFE, Siebert R, Gesk S, Schlegelberger B, Döhner H, Bentz M (2002) Clinicopathological correlation of gains and losses in follicular lymphoma. J Clin Oncol 20:4655–4664
Vose JM (1998) Current approaches to the management of non-Hodgkin's lymphoma. Semin Oncol 25:483–491
Wessendorf S, Fritz B, Wrobel G, Nessling M, Lampel S, Goettel D, Kuepper M, Joos S, Hopman T, Kokocinski F, Döhner H, Bentz M, Schwaenen C, Lichter P (2002) Automated screening for genomic imbalances using matrix-based comparative genomic hybridization. Lab Invest 82:47–60
Wessendorf S, Schwaenen C, Kohlhammer H, Wrobel G, Barth TFE, Nessling M, Moeller P, Döhner H, Lichter P, Bentz M (2003) Hidden gene amplifications in aggressive B-cell non-Hodgkin lymphomas detected by microarray based comparative genomic hybridization. Oncogene, in press
Wilhelm M, Veltman JA, Olshen AB, Jain AN, Moore DH, Presti JC Jr, Kovacs G, Waldman FM (2002) Array-based comparative genomic hybridization for the differential diagnosis of renal cell cancer. Cancer Res 62:957–960
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 1:133–143
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The Deutsche Krebshilfe, the Deutsche Forschungsgemeinschaft, and the Bundesministerium für Bildung und Forschung are gratefully acknowledged for funding our studies focussing on genomic DNA chip hybridization.
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Schwaenen, C., Wessendorf, S., Kestler, H.A. et al. DNA microarray analysis in malignant lymphomas. Ann Hematol 82, 323–332 (2003). https://doi.org/10.1007/s00277-003-0649-6
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DOI: https://doi.org/10.1007/s00277-003-0649-6