title: Clinical and Biologic Significance of MYC Genetic Mutations in De Novo Diffuse Large B-cell Lymphoma.
abstract: MYC is a critical driver oncogene in many cancers, and its deregulation in the forms of translocation and overexpression has been implicated in lymphomagenesis and progression of diffuse large B-cell lymphoma (DLBCL). The MYC mutational profile and its roles in DLBCL are unknown. This study aims to determine the spectrum of MYC mutations in a large group of patients with DLBCL, and to evaluate the clinical significance of MYC mutations in patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy.
  
  
  
  We identified MYC mutations in 750 patients with DLBCL using Sanger sequencing and evaluated the prognostic significance in 602 R-CHOP-treated patients.
  
  
  
  The frequency of MYC mutations was 33.3% at the DNA level (mutations in either the coding sequence or the untranslated regions) and 16.1% at the protein level (nonsynonymous mutations). Most of the nonsynonymous mutations correlated with better survival outcomes; in contrast, T58 and F138 mutations (which were associated with MYC rearrangements), as well as several mutations occurred at the 3' untranslated region, correlated with significantly worse survival outcomes. However, these mutations occurred infrequently (only in approximately 2% of DLBCL). A germline SNP encoding the Myc-N11S variant (observed in 6.5% of the study cohort) was associated with significantly better patient survival, and resulted in reduced tumorigenecity in mouse xenografts.
  
  
  
  Various types of MYC gene mutations are present in DLBCL and show different impact on Myc function and clinical outcomes. Unlike MYC gene translocations and overexpression, most MYC gene mutations may not have a role in driving lymphomagenesis. Clin Cancer Res; 22(14); 3593-605. ©2016 AACR.
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zijun Y
authors.initials: ZY
authors.lastname: Xu-Monette
authors.affiliation: Department of Cancer Biology, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Qipan
authors.initials: Q
authors.lastname: Deng
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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, Texas.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xiao-Xiao
authors.initials: XX
authors.lastname: Wang
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Dehui
authors.initials: D
authors.lastname: Zou
authors.affiliation: San Bortolo Hospital, Vicenza, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Visco
authors.affiliation: Aarhus University Hospital, Aalborg, Denmark.
authors.forename: Karen
authors.initials: K
authors.lastname: Dybkær
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Han
authors.initials: H
authors.lastname: Liang
authors.affiliation: Hospital Universitario Marqués de Valdecilla, Santander, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Montes-Moreno
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: April
authors.initials: A
authors.lastname: Chiu
authors.affiliation: Weill Medical College of Cornell University, New York, New York.
authors.forename: Attilio
authors.initials: A
authors.lastname: Orazi
authors.affiliation: The Methodist Hospital, Houston, Texas.
authors.forename: Youli
authors.initials: Y
authors.lastname: Zu
authors.affiliation: Columbia University Medical Center and New York Presbyterian Hospital, New York, New York.
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Kristy L
authors.initials: KL
authors.lastname: Richards
authors.affiliation: Cleveland Clinic, Cleveland, Ohio.
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, 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: Gundersen Lutheran Health System, La Crosse, Wisconsin.
authors.forename: Ben M
authors.initials: BM
authors.lastname: Parsons
authors.affiliation: Odense University Hospital, Odense, Denmark.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Møller
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sa A
authors.initials: SA
authors.lastname: Wang
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Roberto N
authors.initials: RN
authors.lastname: Miranda
authors.affiliation: Hospital Universitario Marqués de Valdecilla, Santander, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Piris
authors.affiliation: Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Jane N
authors.initials: JN
authors.lastname: Winter
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.affiliation: Department of Cancer Biology, Cleveland Clinic, Cleveland, Ohio. khyoung@mdanderson.org liy2@ccf.org.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. The University of Texas School of Medicine, Graduate School of Biomedical Sciences, Houston, Texas. khyoung@mdanderson.org liy2@ccf.org.
authors.forename: Ken H
authors.initials: KH
authors.lastname: Young
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects / Q000235:genetics*; D011241:Prednisone / Q000627:therapeutic use; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D000069283:Rituximab; D014178:Translocation, Genetic / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D016271:Proto-Oncogene Proteins c-myc; C571759:R-CHOP protocol; D016159:Tumor Suppressor Protein p53; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone