title: MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma.
abstract: MYC rearrangements occur in 5% to 10% of diffuse large B-cell lymphomas (DLBCL) and confer an increased risk to cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (CHOP) and rituximab (R)-CHOP treated patients. We investigated the prognostic relevance of MYC-, BCL2- and BCL6-rearrangements and protein expression in a prospective randomized trial. Paraffin-embedded tumor samples from 442 de novo DLBCL treated within the RICOVER study of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) were investigated using immunohistochemistry and fluorescence in situ hybridization (FISH) to detect protein expression and breaks of MYC, BCL2, and BCL6. Rearrangements of MYC, BCL2, and BCL6 were detected in 8.8%, 13.5%, and 28.7%, respectively. Protein overexpression of MYC (>40%) was encountered in 31.8% of tumors; 79.6% and 82.8% of tumors expressed BCL2 and BCL6, respectively. MYC translocations, MYChigh, BCL2high, and BCL6low protein expressions were associated with inferior survival. In multivariate Cox regression modeling, protein expression patterns of MYC, BCL2 and BCL6, and MYC rearrangements were predictive of outcome and provided prognostic information independent of the International Prognostic Index (IPI) for overall survival and event-free survival. A combined immunohistochemical or FISH/immunohistochemical score predicts outcome in DLBCL patients independent of the IPI and identifies a subset of 15% of patients with dismal prognosis in the high-risk IPI group following treatment with R-CHOP. Registered at http://www.cancer.gov/clinicaltrials: RICOVER trial of the DSHNHL is NCT 00052936.
authors: Department of Clinical Pathology, Robert-Bosch-Krankenhaus and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
authors: Heike
authors: H
authors: Horn
authors: Marita
authors: M
authors: Ziepert
authors: Claudia
authors: C
authors: Becher
authors: Thomas F E
authors: TF
authors: Barth
authors: Heinz-Wolfram
authors: HW
authors: Bernd
authors: Alfred C
authors: AC
authors: Feller
authors: Wolfram
authors: W
authors: Klapper
authors: Michael
authors: M
authors: Hummel
authors: Harald
authors: H
authors: Stein
authors: Martin-Leo
authors: ML
authors: Hansmann
authors: Christopher
authors: C
authors: Schmelter
authors: Peter
authors: P
authors: Möller
authors: Sergio
authors: S
authors: Cogliatti
authors: Michael
authors: M
authors: Pfreundschuh
authors: Norbert
authors: N
authors: Schmitz
authors: Lorenz
authors: L
authors: Trümper
authors: Reiner
authors: R
authors: Siebert
authors: Markus
authors: M
authors: Loeffler
authors: Andreas
authors: A
authors: Rosenwald
authors: German
authors: G
authors: Ott
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D003520:Cyclophosphamide / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D016259:Genes, myc / Q000235:genetics* / Q000502:physiology; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D011241:Prednisone / Q000627:therapeutic use; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000502:physiology; D051560:Proto-Oncogene Proteins c-bcl-6; D016032:Randomized Controlled Trials as Topic; D000069283:Rituximab; D016019:Survival Analysis; D016896:Treatment Outcome; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; C084103:BCL6 protein, human; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051560:Proto-Oncogene Proteins c-bcl-6; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone