title: Impact of Single or Combined Genomic Alterations of TP53, MYC, and BCL2 on Survival of Patients With Diffuse Large B-Cell Lymphomas: A Retrospective Cohort Study.
abstract: MYC and BCL2 translocations as well as TP53 deletion/mutation are known risk factors in diffuse large B-cell lymphoma (DLBCL) but their interplay is not well understood.In this retrospective cohort study, we evaluated the combined prognostic impact of TP53 deletion and mutation status, MYC and BCL2 genomic breaks in tumor samples of 101 DLBCL patients. The cohort included 53 cases with MYC rearrangements (MYC+).TP53 deletions/mutations (TP53+) were found in 32 of 101 lymphomas and were equally distributed between MYC+ and MYC- cases (35.8% vs. 27.1%). TP53+ lymphomas had lower responses to treatment than TP53- (complete remission 34.4% vs. 60.9%; P = 0.01). TP53 alteration was the dominant independent prognostic factor in multivariate analysis (P = 0.01). Overall survival (OS) varied considerably between subgroups with different genomic alterations: Patients with sole MYC translocation, and interestingly, with triple MYC+/BCL2+/TP53+ aberration had favorable outcomes (median OS not reached) similar to patients without genomic alterations (median OS 65 months). In contrast, patients with MYC+/BCL2+/TP53- double-hit lymphomas (DHL) (28 months), MYC+/BCL2-/TP53+ lymphomas (10 months) or sole TP53 mutation/deletion (12 months) had a poor median OS. Our findings demonstrate differences in OS of DLBCL patients depending on absence or presence of single or combined genetic alterations of MYC, BCL2, and TP53. Cooccurrence of TP53 and BCL2 aberrations ameliorated the poor prognostic impact of single TP53+ or BCL2+ in MYC positive patients.This pilot study generates evidence for the complex interplay between the alterations of genetic pathways in DLBCL, which goes beyond the concept of DHL. The variable survival of DLBCL patients dependent on single or combined alterations in the TP53, MYC, and BCL2 genes indicates the need for comprehensive genomic diagnosis.
authors.affiliation: From the Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria (A-IS, CK, IS-K, BS, KW, BM, LM); Division of Hematology and Hemostaseology, Department of Internal Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria (CS, KV, UJ, EP); Division of Palliative Care, Department of Internal Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria (EKM); Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria (DS); Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria (DS); Institute of Pharmacology and Toxicology, Department of Biomedical Sciences, Veterinary University of Vienna, Vienna, Austria (VS); Division of Oncology, Department of Internal Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria (MR); Institute of Pathology and Bacteriology, Wilhelminenspital, Vienna, Austria (AC); Portuguese Institute of Oncology, Haematology Unit, Lisbon, Portugal (MGdS); and Portuguese Institute of Anatomical Pathology, Lisbon, Portugal (JC).
authors.forename: Ana-Iris
authors.initials: AI
authors.lastname: Schiefer
authors.forename: Christoph
authors.initials: C
authors.lastname: Kornauth
authors.forename: Ingrid
authors.initials: I
authors.lastname: Simonitsch-Klupp
authors.forename: Cathrin
authors.initials: C
authors.lastname: Skrabs
authors.forename: Eva Katharina
authors.initials: EK
authors.lastname: Masel
authors.forename: Berthold
authors.initials: B
authors.lastname: Streubel
authors.forename: Katrina
authors.initials: K
authors.lastname: Vanura
authors.forename: Karin
authors.initials: K
authors.lastname: Walter
authors.forename: Brigitta
authors.initials: B
authors.lastname: Migschitz
authors.forename: Dagmar
authors.initials: D
authors.lastname: Stoiber
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
authors.forename: Markus
authors.initials: M
authors.lastname: Raderer
authors.forename: Andreas
authors.initials: A
authors.lastname: Chott
authors.forename: Maria Gomes
authors.initials: MG
authors.lastname: da Silva
authors.forename: Jose
authors.initials: J
authors.lastname: Cabecadas
authors.forename: Leonhard
authors.initials: L
authors.lastname: Müllauer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jäger
authors.forename: Edit
authors.initials: E
authors.lastname: Porpaczy
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012189:Retrospective Studies; D017384:Sequence Deletion; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C000595707:BCL2 protein, human; C489427:MYC protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53