title: Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP.
abstract: MYC dysregulation, including MYC gene rearrangement and Myc protein overexpression, is of increasing clinical importance in diffuse large B-cell lymphoma (DLBCL). However, the roles of MYC and the relative importance of rearrangement vs overexpression remain to be refined. Gaining knowledge about the tumor biology associated with MYC dysregulation is important to understand the roles of MYC and MYC-associated biology in lymphomagenesis. In this study, we determined MYC rearrangement status (n=344) and Myc expression (n=535) in a well-characterized DLBCL cohort, individually assessed the clinical and pathobiological features of patients with MYC rearrangement and Myc protein overexpression, and analyzed the prognosis and gene expression profiling signatures associated with these MYC abnormalities in germinal center B-cell-like and activated B-cell-like DLBCL. Our results showed that the prognostic importance of MYC rearrangement vs Myc overexpression is significantly different in germinal center B-cell-like vs activated B-cell-like DLBCL. In germinal center B-cell-like DLBCL, MYC-rearranged germinal center B-cell-like DLBCL patients with Myc overexpression significantly contributed to the clinical, biological, and prognostic characteristics of the overall Myc-overexpressing germinal center B-cell-like DLBCL group. In contrast, in activated B-cell-like DLBCL, the occurrence, clinical and biological features, and prognosis of Myc overexpression were independent of MYC rearrangement. High Myc levels and Myc-independent mechanisms, either tumor cell intrinsic or related to tumor microenvironment, conferred significantly worse survival to MYC-rearranged germinal center B-cell-like DLBCL patients, even among Myc(high)Bcl-2(high) DLBCL patients. This study provides new insight into the tumor biology and prognostic effects associated with MYC dysregulation and suggest that detection of both MYC translocations and evaluation of Myc and Bcl-2 expression is necessary to predict the prognosis of DLBCL patients.
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Zijun Y
authors.initials: ZY
authors.lastname: Xu-Monette
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Bouthaina S
authors.initials: BS
authors.lastname: Dabaja
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Meifeng
authors.initials: M
authors.lastname: Tu
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ganiraju C
authors.initials: GC
authors.lastname: Manyam
authors.affiliation: University Hospital, Basel, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Sun
authors.affiliation: San Bortolo Hospital, Vicenza, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Visco
authors.affiliation: Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Karen
authors.initials: K
authors.lastname: Dybkaer
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Lihui
authors.initials: L
authors.lastname: Yin
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: April
authors.initials: A
authors.lastname: Chiu
authors.affiliation: Weill Medical College of Cornell University, New York, NY, USA.
authors.forename: Attilio
authors.initials: A
authors.lastname: Orazi
authors.affiliation: The Methodist Hospital, Houston, TX, USA.
authors.forename: Youli
authors.initials: Y
authors.lastname: Zu
authors.affiliation: Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA.
authors.forename: Govind
authors.identifier: http://orcid.org/0000-0001-6250-048X
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Kristy L
authors.identifier: http://orcid.org/0000-0001-5765-6631
authors.initials: KL
authors.lastname: Richards
authors.affiliation: Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hsi
authors.affiliation: University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China.
authors.forename: William W L
authors.initials: WW
authors.lastname: Choi
authors.affiliation: Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: J Han
authors.initials: JH
authors.lastname: van Krieken
authors.affiliation: Asan Medical Center, Ulsan University College of Medicine, Seoul, South Korea.
authors.forename: Jooryung
authors.initials: J
authors.lastname: Huh
authors.affiliation: San Raffaele H Scientific Institute, Milan, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: San Raffaele H Scientific Institute, Milan, Italy.
authors.forename: Andrés J M
authors.initials: AJ
authors.lastname: Ferreri
authors.affiliation: Odense University Hospital, Odense, Denmark.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Møller
authors.affiliation: Gundersen Lutheran Health System, La Crosse, WI, USA.
authors.forename: Ben M
authors.initials: BM
authors.lastname: Parsons
authors.affiliation: Zhejiang University School of Medicine, Second University Hospital, Hangzhou, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Jane N
authors.initials: JN
authors.lastname: Winter
authors.affiliation: Hospital Universitario Marqués de Valdecilla, Santander, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Piris
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: McDonnell
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Roberto N
authors.initials: RN
authors.lastname: Miranda
authors.affiliation: Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|The University of Texas School of Medicine, Graduate School of Biomedical Sciences, Houston, TX, USA.
authors.forename: Ken H
authors.initials: KH
authors.lastname: Young
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D015321:Gene Rearrangement; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000008:administration & dosage; D011379:Prognosis; D016016:Proportional Hazards Models; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D000069283:Rituximab / Q000008:administration & dosage; D059467:Transcriptome; D014750:Vincristine / Q000008:administration & dosage
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone