RSS-Feed abonnieren
DOI: 10.1055/s-2004-831850
© Georg Thieme Verlag Stuttgart · New York
Expressionsmuster und prognostische Bedeutung von CD24, p53 und p21 in Lymphomen
Eine Gewebe-Mikroarray-Studie an über 600 Non-Hodgkin-LymphomenExpression profile and prognostic significance of CD24, p53 and p21 in Non-Hodgkin-LymphomasPublikationsverlauf
eingereicht: 4.6.2004
akzeptiert: 25.8.2004
Publikationsdatum:
28. September 2004 (online)
Hintergrund und Fragestellung: Gewebemikroarrays („tissue microarrays“, TMA) erlauben eine simultane, rasche und standardisierte In-situ-Untersuchung von bis zu 1000 verschiedenen Gewebeproben auf einem Objektträger. In dieser Studie untersuchten wir das Expressionsprofil und die prognostische Bedeutung von CD24, p53 und p21 an einem Non-Hodgkin-Lymphom-Gewebemikroarray.
Methodik: 603 gut dokumentierte Non-Hodgkin-Lymphome wurden in ein Array-Format gebracht (341 diffus großzellige B-Zell-Lymphome, 86 follikuläre Lymphome, 81 chronische lymphatische Leukämien/kleinlymphozytische Lymphome, 51 primär mediastinale diffus großzellige B-Zell-Lymphome, 26 Mantelzelllymphome, 8 lymphoplasmozytische Lymphome, 8 nicht näher spezifizierte T-Zell-Lymphome und 2 Burkitt-Lymphome). Die Expression von CD24, p53 und p21 wurde immunhistochemisch analysiert und semiquantitativ ausgewertet. Der Immunphänotyp p53+/p21- diente als Surrogatmarker (Δ-p53) für p53-Genmutationen. Bei den diffus großzelligen B-Zell-Lymphomen wurde die Markerexpression mit klinischen Daten und dem Gesamtüberleben korreliert.
Ergebnis: 473 von 522 aller auswertbaren Non-Hodgkin-Lymphome (91%) waren CD24 positiv. Die CD24-Expression war nicht mit dem Gesamtüberleben assoziiert. Ein Δ-p53 wurde in 70 von 539 auswertbaren Lymphomen (13%) gefunden. Am häufigsten fand sich ein Δp53 bei diffus großzelligen B-Zell-Lymphomen (21%). In der multivariaten Cox-Regressions-Analyse waren ein hoher internationaler prognostischer Index sowie ein Δp53 unabhängige Parameter für ein schlechtes Gesamtüberleben.
Folgerung: Die Gewebemikroarray-Technik erlaubt auch in der Lymphomforschung eine bisher in dieser Form nicht mögliche, effiziente, simultane und weitgehend standardisierte klinisch-pathologische Analyse großer Patientengruppen. Immunhistochemisch bestimmtes Δp53 ist ein unabhängiger negativer Prognosefaktor bei diffus großzelligen B-Zell-Lymphomen und kann problemlos routinemäßig bestimmt werden.
Background and objective: Tissue microarrays allow the simultanous, rapid and standardized in-situ analysis of up to 1000 different tissue samples on a single glass slide. We investigated the expression profil and the prognostic significance of CD24, p53 and p21 using a Non-Hodgkin-Lymphoma tissue microarray.
Methods: Over 600 well documented Non-Hodgkin-Lymphomas, consisting of 341 diffuse large B-cell lymphomas, 86 follicular lymphomas, 81 chronic lymphatic leukemias/small lymphocytic lymphomas, 51 primary mediastinal diffuse large B-cell lymphomas, 26 mantle cell lymphomas, 8 lymphoplasmocytic lymphomas, 8 T-cell-lymphomas NOS und 2 Burkitt lymphomas were brought into array format. The expression of CD24, p53 and p21 was analysed semiquantitatively by immunohistochemistry. The immunophenotype p53+/p21- (Δp53) was used as a surrogat for p53 gene mutations. The expression profile was compared to clinical data and the overall survival in the subgroup of diffuse large B-cell lymphomas.
Results: 91% of the analyzed Non-Hodgkin-lymphomas (473 of 522 cases) showed CD24 positivity. CD24 Expression was not associated with survival. Δp53 was found in thirteen percent of all lymphomas (70 of 539 cases), the subgroup of the diffuse large B-cell lymphomas demonstrated the highest Δp53 (21%). In a multivariate cox regression analysis, a high international prognostic index and Δp53 were independent markers of bad survival.
Conclusion: The TMA-technology allows also in lymphoma research the simultanous, cost-effective and standardized analysis of large patient cohorts. Δp53 revealed as an independent negative prognostic factor in diffuse large B-cell lymphomas. It can easily be determined in daily routine practice.
Literatur
- 1 Aigner S, Sthoeger Z M, Fogel M. et al . CD24, a mucin-type glycoprotein, is a ligand for P-selectin on human tumor cells. Blood. 1997; 89 3385-3395
- 2 Alizadeh A A, Eisen M B, Davis R E. et al . Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000; 403 503-511
- 3 Benkerrou M, Jais J P, Leblond V. et al . Anti-B-cell monoclonal antibody treatment of severe posttransplant B-lymphoproliferative disorder: prognostic factors and long-term outcome. Blood. 1998; 92 3137-3147
- 4 Chilosi M, Doglioni C, Magalini A. et al . p21/WAF1 cyclin-kinase inhibitor expression in non-Hodgkin’s lymphomas: a potential marker of p53 tumor-suppressor gene function. Blood. 1996; 88 4012-4020
- 5 Go J H. Expressions of the CIP/KIP family of CDK inhibitor proteins in primary intestinal large B-cell lymphomas: correlation with clinical outcomes. Pathol Res Pract. 2002; 198 741-746
- 6 Hans C P, Weisenburger D D, Greiner T C. et al . Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004; 103 275-282
- 7 Hough M R, Chappel M S, Sauvageau G, Takei F, Kay R, Humphries R K. Reduction of early B lymphocyte precursors in transgenic mice overexpressing the murine heat-stable antigen. J Immunol. 1996; 156 479-488
- 8 Jackson N, Ling N R, Ball J, Bromidge E, Nathan P D, Franklin I M. An analysis of myeloma plasma cell phenotype using antibodies defined at the IIIrd International Workshop on Human Leucocyte Differentiation Antigens. Clin Exp Immunol. 1988; 72 351-356
- 9 Jung K C, Park W S, Kim H J. et al . TCR-independent and caspase-independent apoptosis of murine thymocytes by CD24 cross-linking. J Immunol. 2004; 172 795-802
- 10 Kay R, Rosten P M, Humphries R K. CD24, a signal transducer modulating B cell activation responses, is a very short peptide with a glycosyl phosphatidylinositol membrane anchor. J Immunol. 1991; 147 1412-1416
- 11 Kristiansen G, Denkert C, Schluns K, Dahl E, Pilarsky C, Hauptmann S. CD24 is expressed in ovarian cancer and is a new independent prognostic marker of patient survival. Am J Pathol. 2002; 161 1215-1221
- 12 Kristiansen G, Pilarsky C, Pervan J. et al . CD24 expression is a significant predictor of PSA relapse and poor prognosis in low grade or organ confined prostate cancer. Prostate. 2004; 58 183-192
- 13 Kristiansen G, Schluns K, Yongwei Y, Denkert C, Dietel M, Petersen I. CD24 is an independent prognostic marker of survival in nonsmall cell lung cancer patients. Br J Cancer. 2003; 88 231-236
- 14 Kristiansen G, Winzer K J, Mayordomo E. et al . CD24 expression is a new prognostic marker in breast cancer. Clin Cancer Res. 2003; 9 4906-4913
- 15 Lavabre-Bertrand T, Duperray C, Brunet C. et al . Quantification of CD24 and CD45 antigens in parallel allows a precise determination of B-cell maturation stages: relevance for the study of B-cell neoplasias. Leukemia. 1994; 8 402-408
- 16 Leroy K, Haioun C, Lepage E. et al . p53 gene mutations are associated with poor survival in low and low-intermediate risk diffuse large B-cell lymphomas. Ann Oncol. 2002; 13 1108-1115
- 17 Lo Coco F, Gaidano G, Louie D C, Offit K, Chaganti R S, Dalla-Favera R. p53 mutations are associated with histologic transformation of follicular lymphoma. Blood. 1993; 82 2289-2295
- 18 Maestro R, Gloghini A, Doglioni C. et al . Human non-Hodgkin’s lymphomas overexpress a wild-type form of p53 which is a functional transcriptional activator of the cyclin-dependent kinase inhibitor p21. Blood. 1997; 89 2523-2528
- 19 Pileri S A, Dirnhofer S, Went P. et al . Diffuse large B-cell lymphoma: one or more entities? Present controversies and possible tools for its subclassification. Histopathology. 2002; 41 482-509
- 20 Schuurman H J, Huppes W, Verdonck L F, Van Baarlen J, Van Unnik J A. Immunophenotyping of non-Hodgkin’s lymphoma. Correlation with relapse-free survival. Am J Pathol. 1988; 131 102-111
- 21 Slee E A, O’Connor D J, Lu X. To die or not to die: how does p53 decide?. Oncogene. 2004; 23 2809-2818
- 22 Suzuki T, Kiyokawa N, Taguchi T, Sekino T, Katagiri Y U, Fujimoto J. CD24 induces apoptosis in human B cells via the glycolipid-enriched membrane domains/rafts-mediated signaling system. J Immunol. 2001; 166 5567-5577
- 23 Taguchi T, Kiyokawa N, Mimori K. et al . Pre-B cell antigen receptor-mediated signal inhibits CD24-induced apoptosis in human pre-B cells. J Immunol. 2003; 170 252-260
- 24 Torhorst J, Bucher C, Kononen J. et al . Tissue microarrays for rapid linking of molecular changes to clinical endpoints. Am J PatholUBL>. 2001; 159 2249-2256
- 25 Tzankov A, Pehrs A C, Zimpfer A. et al . Prognostic significance of CD44 expression in diffuse large B cell lymphoma of activated and germinal centre B cell-like types: a tissue microarray analysis of 90 cases. J Clin Pathol. 2003; 56 747-752
- 26 Villuendas R, Pezzella F, Gatter K. et al . p21WAF1/CIP1 and MDM2 expression in non-Hodgkin’s lymphoma and their relationship to p53 status: a p53+, MDM2-, p21-immunophenotype associated with missense p53 mutations. J Pathol. 1997; 181 51-61
- 27 Williams L A, McLellan A D, Summers K L, Sorg R V, Fearnley D B, Hart D N. Identification of a novel dendritic cell surface antigen defined by carbohydrate specific CD24 antibody cross-reactivity. Immunology. 1996; 89 120-125
- 28 Zettl A, Meister S, Katzenberger T. et al . Immunohistochemical analysis of B-cell lymphoma using tissue microarrays identifies particular phenotypic profiles of B-cell lymphomas. Histopathology. 2003; 43 209-219
- 29 Zimpfer A, Went P, Tzankov A. et al . Rare Expression of KIT (CD117) in Lymphomas: a tissue microarray study of 1166 cases. Histopathology. 2004; , in press
Priv.-Doz. Dr. med. Stephan Dirnhofer
Institut für Pathologie, Universität Basel
Schönbeinstraße 40
CH-4031 Basel
Telefon: 0041/61/2652789
Fax: 0041/61/2653194
eMail: sdirnhofer@uhbs.ch