title: Prognostic Significance of Diffuse Large B-Cell Lymphoma Cell of Origin Determined by Digital Gene Expression in Formalin-Fixed Paraffin-Embedded Tissue Biopsies.
abstract: OBJECTIVE
  To evaluate the prognostic impact of cell-of-origin (COO) subgroups, assigned using the recently described gene expression-based Lymph2Cx assay in comparison with International Prognostic Index (IPI) score and MYC/BCL2 coexpression status (dual expressers).
  
  
  METHODS
  Reproducibility of COO assignment using the Lymph2Cx assay was tested employing repeated sampling within tumor biopsies and changes in reagent lots. The assay was then applied to pretreatment formalin-fixed paraffin-embedded tissue (FFPET) biopsies from 344 patients with de novo diffuse large B-cell lymphoma (DLBCL) uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the British Columbia Cancer Agency. MYC and BCL2 protein expression was assessed using immunohistochemistry on tissue microarrays.
  
  
  RESULTS
  The Lymph2Cx assay provided concordant COO calls in 96% of 49 repeatedly sampled tumor biopsies and in 100% of 83 FFPET biopsies tested across reagent lots. Critically, no frank misclassification (activated B-cell-like DLBCL to germinal center B-cell-like DLBCL or vice versa) was observed. Patients with activated B-cell-like DLBCL had significantly inferior outcomes compared with patients with germinal center B-cell-like DLBCL (log-rank P < .001 for time to progression, progression-free survival, disease-specific survival, and overall survival). In pairwise multivariable analyses, COO was associated with outcomes independent of IPI score and MYC/BCL2 immunohistochemistry. The prognostic significance of COO was particularly evident in patients with intermediate IPI scores and the non-MYC-positive/BCL2-positive subgroup (log-rank P < .001 for time to progression).
  
  
  CONCLUSIONS
  Assignment of DLBCL COO by the Lymph2Cx assay using FFPET biopsies identifies patient groups with significantly different outcomes after R-CHOP, independent of IPI score and MYC/BCL2 dual expression.
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ. dscott8@bccancer.bc.ca.
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: Anja
authors.initials: A
authors.lastname: Mottok
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ennishi
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: George W
authors.initials: GW
authors.lastname: Wright
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: Pedro
authors.initials: P
authors.lastname: Farinha
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: Susana
authors.initials: S
authors.lastname: Ben-Neriah
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: Robert
authors.initials: R
authors.lastname: Kridel
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: Garrett S
authors.initials: GS
authors.lastname: Barry
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Hother
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: Pau
authors.initials: P
authors.lastname: Abrisqueta
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: Merrill
authors.initials: M
authors.lastname: Boyle
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: Barbara
authors.initials: B
authors.lastname: Meissner
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: Adele
authors.initials: A
authors.lastname: Telenius
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Savage
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Sehn
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: Graham W
authors.initials: GW
authors.lastname: Slack
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: Christian
authors.initials: C
authors.lastname: Steidl
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Connors
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Rimsza
authors.affiliation: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ.
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001706:Biopsy; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000737:chemistry / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D016612:Paraffin Embedding; D011241:Prednisone / Q000627:therapeutic use; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis; D000069283:Rituximab; D046888:Tissue Array Analysis; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; C489427:MYC protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone