Abstract
To identify genes that are associated with progression of malignant lymphoma, the expression profiles of 18 432 genes were analyzed in diffuse large B‐cell lymphomas at early (stages I and II, 6 cases) and advanced stages (stages III and IV, 9 cases) by means of cDNA microarrays. By comparing expression profiles between localized and advanced lymphomas, a number of genes that were differentially expressed were identified: 48 genes with increased expression and 30 genes with reduced expression in advanced‐stage diffuse large B‐cell lymphomas. Increased expression of MPHOSPH1, RUVBL1, CHN2, PSA and CDC10 genes, and reduced expression of COL1A2, COL4A1, FBLN5, CLECSF6, MIC2, CAV1 and S100A10 genes in the advanced lymphoma group were confirmed by semi‐quantitative reverse transcription‐PCR. RUVBL1 and PSA expression was further confirmed by real‐tune quantitative PCR, whose results paralleled the microarray data. The highly expressed genes encode proteins that promote cell proliferation and the genes with reduced expression encode adhesion proteins and target protein for cytotoxic T‐lymphocytes. These findings suggested that analysis with cDNA microarrays is a useful approach for identifying genes related to tumor progression and their products could be potential tumor markers or disease‐specific targets for anti‐tumor therapy.
Keywords: Microarray, Expression profile, Diffuse large B‐cell lymphoma, Stage, Progression
Full Text
The Full Text of this article is available as a PDF (7.1 MB).
REFERENCES
- 1. ) Harris , N. L. , Jaffe , E. S. , Stein , H. , Banks , P. M. , Chan , J. K. C. , Cleary , M. L. , Delsol , G. , Wolf‐Peeters , C. D. , Falini , B. , Gatter , K. C. , Grogan , T. M. , Isaacson , P. G. , Knowles , D. M. , Mason , D. Y. , Muller‐Hermelink , H. K. , Pileri , S. A. , Piris , M. A. , Ralfkiaer , E. and Warnke , R. A.A revised European‐American classification of lymphoid neoplasms: a proposal from the international lymphoma study group . Blood , 84 , 1361 – 1392 ( 1994. ). [PubMed] [Google Scholar]
- 2. ) Pittaluga , S. , Bijnens , L. , Teodorovic , I. , Hagenbeek , A. , Meerwaldt , J. H. , Somers , R. , Thomas , J. , Noordijk , E. M. and De Wolf‐Peeters , C.Clinical analysis of 670 cases in two trials of the European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group subtyped according to the Revised European‐American Classification of Lymphoid Neoplasms: a comparison with the Working Formulation . Blood , 87 , 4358 – 4367 ( 1996. ). [PubMed] [Google Scholar]
- 3. ) The International Non‐Hodgkin's Lymphoma Prognostic Factors Project . A predictive model for aggressive non‐Hodgkin's lymphoma . N. Engl. J. Med. , 329 , 987 – 994 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 4. ) Carbone , P. P. , Kaplan , H. S. , Musshoff , K. , Smithers , D. W. and Tubiana , M.Report of the committee on Hodgkin's disease staging classification . Cancer Res. , 31 , 1860 – 1861 ( 1971. ). [PubMed] [Google Scholar]
- 5. ) Offit , K. , Lo Coco , F. , Louie , D. C. , Parsa , N. Z. , Leung , D. , Portlock , C. , Ye , B. H. , Lista , F. , Filippa , D. A. , Rosenbaum , A. , Ladanyi , M. , Jhanwar , S. , Dalla‐Favera , R. and Chaganti , R. S. K.Rearrangement of the bcl–6 gene as a prognostic marker in diffuse large‐cell lymphoma . N. Engl. J. Med. , 331 , 74 – 80 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 6. ) Kramer , M. H. , Hermans , J. , Wijburg , E. , Philippe , K. , Geelen , E. , van Krieken , J. H. , de Jong , D. , Maartense , E. , Schuuring , E. and Kluin , P. M.Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B‐cell lymphoma . Blood , 92 , 3152 – 3162 ( 1998. ). [PubMed] [Google Scholar]
- 7. ) Seymour , J. F. , Talpaz , M. , Cabanillas , F. , Wetzler , M. and Kurzrock , R.Serum interleukin–6 levels correlate with prognosis in diffuse large‐cell lymphoma . J. Clin. Oncol. , 13 , 575 – 582 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 8. ) Stauder , R. , Eisterer , W. , Thaler , J. and Gunthert , U.CD44 variant isoforms in non‐Hodgkin's lymphoma: a new independent prognostic factor . Blood , 85 , 2885 – 2899 ( 1995. ). [PubMed] [Google Scholar]
- 9. ) Miller , T. P. , Grogan , T. M. , Dahlberg , S. , Spier , C. M. , Braziel , R. M. , Banks , P. M. , Foucar , K. , Kjeldsberg , C. R. , Levy , N. , Nathwani , B. N. , Schnitzer , B. , Tubbs , R. R. , Gaynor , E. R. and Fisher , R. I.Prognostic significance of the Ki–67–associated proliferative antigen in aggressive non‐Hodgkin's lymphomas: a prospective Southwest Oncology Group trial . Blood , 83 , 1460 – 1466 ( 1994. ). [PubMed] [Google Scholar]
- 10. ) DeRisi , J. , Penland , L. , Brown , P. O. , Bittner , M. L. , Meltzer , P. S. , Ray , M. , Chen , Y. , Su , Y. A. and Trent , J. M.Use of a cDNA microarray to analyse gene expression patterns in human cancer . Nat. Genet. , 14 , 457 – 460 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 11. ) Alizadeh , A. A. , Eisen , M. B. , Davis , R. E. , Ma , C. , Losses , I. S. , Rosenwald , A. , Boldrick , J. C. , Sabet , H. , Tran , T. , Yu , X. , Powell , J. I. , Yang , L. , Marti , G. E. , Moore , T. , Hudson , J. , Jr. , Lu , L. , Lewis , D. B. , Tibshirani , R. , Sherlock , G. , Chan , W. C. , Greiner , T. C. , Weisenburger , D. D. , Armitage , J. O. , Warnke , R. , Levy , R. , Wilson , W. , Grever , M. R. , Byrd , J. C. , Botstein , D. , Brown , P. O. and Staudt , L. M.Distinct types of diffuse large B‐cell lymphoma identified by gene expression profiling . Nature , 403 , 503 – 511 ( 2000. ). [DOI] [PubMed] [Google Scholar]
- 12. ) Luo , L. , Salunga , R. C. , Guo , H. , Bittner , A. , Joy , K. C. , Galindo , J. E. , Xiao , H. , Rogers , K. E. , Wan , J. S. , Jackson , M. R. and Erlander , M. G.Gene expression profiles of laser‐captured adjacent neuronal subtypes . Nat. Med. , 5 , 117 – 122 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 13. ) Westendorf , J. M. , Rao , P. N. and Gerace , L.Cloning of cDNA for M‐phase phosphoproteins recognized by the MPM2 monoclonal antibody and determination of the phosphorylated epitope . Proc. Natl. Acad. Sci. USA , 91 , 714 – 718 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. ) Nakatsuru , S. , Sudo , K. and Nakamura , Y.Molecular cloning of a human cDNA homologous to CDC10 in Saccharomyces cerevisiae . Biochem. Biophys. Res. Commun. , 202 , 82 – 87 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 15. ) Shea , J. E. , Toyn , J. H. and Johnston , L. H.The budding yeast U5 snRNP Prp8 is a highly conserved protein which links RNA splicing with cell cycle progression . Nucleic Acids Res. , 22 , 5555 – 5564 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. ) Wood , M. A. , McMahon , S. B. and Cole , M. D.An ATPase/helicase complex is an essential cofactor for oncogenic transformation by c‐Myc . Mol. Cell , 5 , 321 – 330 ( 2000. ). [DOI] [PubMed] [Google Scholar]
- 17. ) Bauer , A. , Huber , O. and Kemler , R.Pontin 52, an interaction partner of beta‐catenin, binds to the TATA box binding protein . Proc. Natl. Acad. Sci. USA , 95 , 14787 – 14792 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. ) Leung , T. , How , B. E. , Manser , E. and Lim , L.Cerebellar bata 2–chimaerin, a GTPase‐activating protein for p21 rasrelated rac is specifically expressed in granule cells and has a unique N‐terminal SH2 domain . J. Biol. Chem. , 269 , 12888 – 12892 ( 1994. ). [PubMed] [Google Scholar]
- 19. ) Joneson , T. , McDonough , M. , Bar‐Sagi , D. and Van Aelst , L.RAC regulation of actin polymerization and proliferation by a pathway distinct from Jun kinase . Science , 274 , 1374 – 1376 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 20. ) Snell , K.Enzymes of serine metabolism in normal, developing and neoplastic rat tissues . Adv. Enzyme Regul. , 22 , 325 – 400 ( 1984. ). [DOI] [PubMed] [Google Scholar]
- 21. ) Travers , H. , French , N. S. and Norton , J. D.Suppression of tumorigenicity in Ras‐transformed fibroblasts by alpha 2(1) collagen . Cell Growth Differ. , 7 , 1353 – 1360 ( 1996. ). [PubMed] [Google Scholar]
- 22. ) Trueb , B. and Odermatt , B. F.Loss of type VI collagen in experimental and most spontaneous human fibrosarcomas . Int. J. Cancer , 86 , 331 – 336 ( 2000. ). [DOI] [PubMed] [Google Scholar]
- 23. ) Apte , S. S. , Olsen , B. R. and Murphy , G.The gene structure of tissue inhibitor of metalloproteinases (TIMP)‐3 and its inhibitory activities define the distinct TIMP gene family . J. Biol. Chem. , 270 , 14313 – 14318 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 24. ) Andreu , T. , Beckers , T. , Thoenes , E. , Hilgard , P. and von Melchner , H.Gene trapping identifies inhibitors of oncogenic transformation. The tissue inhibitor of metalloproteinases–3 (TIMP3) and collagen type I alpha2 (COL1A2) are epidermal growth factor‐regulated growth repressers . J. Biol. Chem. , 273 , 13848 – 13854 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 25. ) Nakamura , T. , Ruiz‐Lozano , P. , Lindner , V. , Yabe , D. , Taniwaki , M. , Furukawa , Y. , Kobuke , K. , Tashiro , K. , Lu , Z. , Andon , N. L. , Schaub , R. , Matsumori , A. , Sasayama , S. , Chien , K. R. and Honjo , T.DANCE, a novel secreted RGD protein expressed in developing, atherosclerotic, and balloon‐injured arteries . J. Biol. Chem. , 274 , 22476 – 22483 ( 1999. ). [DOI] [PubMed] [Google Scholar]
- 26. ) Bates , E. E. , Fournier , N. , Garcia , E. , Valladeau , J. , Durand , I. , Pin , J. J. , Zurawski , S. M. , Patel , S. , Abrams , J. S. , Lebecque , S. , Garrone , P. and Saeland , S.APCs express DCIR, a novel C‐type lectin surface receptor containing an immunoreceptor tyrosine‐based inhibitory motif . J. Immunol. , 163 , 1973 – 1983 ( 1999. ). [PubMed] [Google Scholar]
- 27. ) Engelman , J. A. , Zhang , X. , Galbiati , F. , Volonte , D. , Sotgia , F. , Pestell , R. G. , Minetti , C. , Scherer , P. E. , Okamoto , T. and Lisanti , M. P.Molecular genetics of the caveolin gene family: implications for human cancers, diabetes, Alzheimer disease, and muscular dystrophy . Am. J. Hum. Genet. , 63 , 1578 – 1587 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. ) Nakao , M. , Shichijo , S. , Imaizumi , T. , Inoue , Y. , Matsunaga , K. , Yamada , A. , Kikuchi , M. , Tsuda , N. , Ohta , K. , Takamori , S. , Yamana , H. , Fujita , H. and Itoh , K.Identification of a gene coding for a new squamous cell carcinoma antigen recognized by the CTL . J. Immunol. , 164 , 2565 – 2574 ( 2000. ). [DOI] [PubMed] [Google Scholar]