title: High levels of topoisomerase IIalpha protein expression in diffuse large B-cell lymphoma are associated with high proliferation, germinal center immunophenotype, and response to treatment.
abstract: Gene copy number and protein expression of topoisomerase IIalpha were correlated to benefit from anthracyclines in various tumors. A retrospective series of 69 patients with DLBCL managed with CHOP chemotherapy were studied for immunohistochemical TopoIIalpha expression and numerical gene abnormalities by fluorescent in situ hybridization (FISH). The results were analyzed in relation to the expression of cell cycle proteins (Ki67, p53, HDM2, p21, p14, pRb, p16, and cyclins A, B1, D1, D2, D3, and E) and BCL6/CD10/MUM1/CD138 B-cell differentiation immunophenotype and outcome. High levels of TopoIIalpha protein were found in 91% of DLBCL cases. No evidence of TopoIIalpha gene amplification or deletion was found. The TopoIIalpha expression showed significant positive correlations with the proliferation index Ki67 (p = 0.002), cell cycle proteins pRb and cyclin D2 (p = 0.018 and p = 0.028, respectively), and the germinal center proteins bcl6 and CD10 (p = 0.010 and p < 0.0001, respectively). TopoIIalpha expression was significantly higher in germinal center B-cell like (GCB) DLBCL than in non-germinal center B-cell like (non-GCB) DLBCL (p = 0.048). TopoIIalpha protein was significantly associated with response to chemotherapy (chi(2), p = 0.024), but not with relapse-free or overall survival (p = 0.5). On multivariate analysis, only stage of disease retained independent prognostic significance (HR 0.33 for early stage, p = 0.008). Although TopoIIa gene copy number abnormalities were not found in DLBCL, high levels of protein expression are associated with GCB-cell differentiation immunophenotype, high proliferation, and response to treatment.
authors.affiliation: Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Pentheroudakis
authors.forename: Anna
authors.initials: A
authors.lastname: Goussia
authors.forename: Evangelos
authors.initials: E
authors.lastname: Voulgaris
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Nikolaidis
authors.forename: Evaggelia
authors.initials: E
authors.lastname: Ioannidou
authors.forename: Alexandra
authors.initials: A
authors.lastname: Papoudou-Bai
authors.forename: Konstantina
authors.initials: K
authors.lastname: Grepi
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Kanavaros
authors.forename: Nicholas
authors.initials: N
authors.lastname: Pavlidis
authors.forename: Maria
authors.initials: M
authors.lastname: Bai
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D003520:Cyclophosphamide / Q000627:therapeutic use; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D005784:Gene Amplification; D018858:Germinal Center / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D006801:Humans; D007124:Immunoenzyme Techniques; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011239:Prednisolone / Q000627:therapeutic use; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone; D004250:DNA Topoisomerases, Type II