title: Rearrangements of MYC gene facilitate risk stratification in diffuse large B-cell lymphoma patients treated with rituximab-CHOP.
abstract: In order to address the debatable prognostic role of MYC rearrangements in diffuse large B-cell lymphoma patients treated with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, we evaluated MYC rearrangements by fluorescence in situ hybridization in 563 cases using break-apart probes and IGH/MYC dual-fusion probes. Concurrent BCL2 and BCL6 aberrations were also assessed. Data were correlated with clinicopathological variables and prognostic parameters. MYC rearrangements were observed in 39/432 evaluable cases (9%), including 4 rearrangements detectable only with the dual-fusion probes, 15 detectable only with the break-apart probes and 20 detectable with both dual-fusion probes and break-apart probes. MYC rearrangements correlated with germinal center B-cell origin (P=0.02), MYC protein expression (P=0.032), and larger tumor mass size (P=0.0003). Patients with MYC rearrangements were more likely to be treatment resistant (P<0.0001). All types of MYC rearrangements were associated with poorer disease-specific survival, that is, 20/39 dead, median disease-specific survival 42 months, compared with 98/393 dead among the non-rearranged cases, median disease-specific survival not reached (P=0.0002). Cases with MYC rearrangements that overexpressed MYC protein were at risk with respect to disease-specific survival independent of the International Prognostic Index (P=0.046 and P<0.001, respectively). Presence of concurrent BCL2 aberrations but not of BCL6 aberrations was prognostically additive. Radiotherapy seemed to diminish the prognostic effects of MYC rearrangements in diffuse large B-cell lymphoma patients since only 2/10 irradiated patients with MYC rearrangements died of/with disease, compared with 16/28 non-irradiated patients with MYC rearrangements. We conclude that MYC rearrangements add prognostic information for individual risk estimation and such cases might represent a distinct, biologically determined disease subgroup.
authors: 1] Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA [2] Department of Pathology, University Hospital, Basel, Switzerland.
authors: Alexandar
authors: A
authors: Tzankov
authors: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Zijun Y
authors: ZY
authors: Xu-Monette
authors: Department of Pathology, University Hospital, Basel, Switzerland.
authors: Marc
authors: M
authors: Gerhard
authors: Department of Hematology, San Bortolo Hospital, Vicenza, Italy.
authors: Carlo
authors: C
authors: Visco
authors: Department of Pathology, University Hospital, Basel, Switzerland.
authors: Stephan
authors: S
authors: Dirnhofer
authors: Department of Pathology, University Hospital, Basel, Switzerland.
authors: Nora
authors: N
authors: Gisin
authors: Department of Pathology, Aalborg University Hospital, Aalborg, Denmark.
authors: Karen
authors: K
authors: Dybkaer
authors: Department of Pathology, Weill Medical College of Cornell University, New York, NY, USA.
authors: Attilio
authors: A
authors: Orazi
authors: Department of Pathology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA.
authors: Govind
authors: G
authors: Bhagat
authors: Department of Hematology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors: Kristy L
authors: KL
authors: Richards
authors: Department of Clinical Pathology, Cleveland Clinic, Cleveland, OH, USA.
authors: Eric D
authors: ED
authors: Hsi
authors: Department of Pathology, University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China.
authors: William W L
authors: WW
authors: Choi
authors: Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: J Han
authors: JH
authors: van Krieken
authors: Unit of Lymphoid Malignancies, San Raffaele H Scientific Institute, Milan, Italy.
authors: Maurilio
authors: M
authors: Ponzoni
authors: Unit of Lymphoid Malignancies, San Raffaele H Scientific Institute, Milan, Italy.
authors: Andrés J M
authors: AJ
authors: Ferreri
authors: Department of Pathology, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
authors: Qing
authors: Q
authors: Ye
authors: Department of Hematology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors: Jane N
authors: JN
authors: Winter
authors: Department of Hematology, Gundersen Lutheran Health System, La Crosse, WI, USA.
authors: John P
authors: JP
authors: Farnen
authors: Department of Pathology, Hospital Universitario Marqués de Valdecilla/IFIMAV, Santander, Spain.
authors: Miguel A
authors: MA
authors: Piris
authors: Department of Pathology, Odense University Hospital, Odense, Denmark.
authors: Michael B
authors: MB
authors: Møller
authors: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: M James
authors: MJ
authors: You
authors: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Timothy
authors: T
authors: McDonnell
authors: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: L Jeffrey
authors: LJ
authors: Medeiros
authors: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Ken H
authors: KH
authors: Young
mesh_terms: D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000627:therapeutic use; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D018570:Risk Assessment; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D016271:Proto-Oncogene Proteins c-myc; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone