title: Molecular classification of MYC-driven B-cell lymphomas by targeted gene expression profiling of fixed biopsy specimens.
abstract: Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) are aggressive tumors of mature B cells that are distinguished by a combination of histomorphological, phenotypic, and genetic features. A subset of B-cell lymphomas, however, has one or more characteristics that overlap BL and DLBCL, and are categorized as B-cell lymphoma unclassifiable, with features intermediate between BL and DLBCL (BCL-U). Molecular analyses support the concept that there is a biological continuum between BL and DLBCL that includes variable activity of MYC, an oncoprotein once thought to be only associated with BL, but now recognized as a major predictor of survival among patients with DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). We tested whether a targeted expression profiling panel could be used to categorize tumors as BL and DLBCL, resolve the molecular heterogeneity of BCL-U, and capture MYC activity using RNA from formalin-fixed, paraffin-embedded biopsy specimens. A diagnostic molecular classifier accurately predicted pathological diagnoses of BL and DLBCL, and provided more objective subclassification for a subset of BCL-U and genetic double-hit lymphomas as molecular BL or DLBCL. A molecular classifier of MYC activity correlated with MYC IHC and stratified patients with primary DLBCL treated with R-CHOP into high- and low-risk groups. These results establish a framework for classifying and stratifying MYC-driven, aggressive, B-cell lymphomas on the basis of quantitative molecular profiling that is applicable to fixed biopsy specimens.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; Northern Institute for Cancer Research, Newcastle Upon Tyne, United Kingdom.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Carey
authors.affiliation: Department of Computational Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gusenleitner
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Kovach
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kluk
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Heather H
authors.initials: HH
authors.lastname: Sun
authors.affiliation: Northern Institute for Cancer Research, Newcastle Upon Tyne, United Kingdom.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Crossland
authors.affiliation: Northern Institute for Cancer Research, Newcastle Upon Tyne, United Kingdom.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Bacon
authors.affiliation: Northern Institute for Cancer Research, Newcastle Upon Tyne, United Kingdom.
authors.forename: Vikki
authors.initials: V
authors.lastname: Rand
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Paola
authors.initials: P
authors.lastname: Dal Cin
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Long P
authors.initials: LP
authors.lastname: Le
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Aliyah R
authors.initials: AR
authors.lastname: Sohani
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Shipp
authors.affiliation: Department of Computational Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Stefano
authors.initials: S
authors.lastname: Monti
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address: srodig@partners.org.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
mesh_terms: D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D002051:Burkitt Lymphoma / Q000145:classification* / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D003520:Cyclophosphamide; D004317:Doxorubicin; D005557:Formaldehyde; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000145:classification* / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010232:Paraffin; D016612:Paraffin Embedding; D011241:Prednisone; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D000069283:Rituximab; D016019:Survival Analysis; D016707:Tissue Fixation; D014750:Vincristine
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; C571759:R-CHOP protocol; D005557:Formaldehyde; D000069283:Rituximab; D014750:Vincristine; D010232:Paraffin; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone