Double-hit gene expression signature defines a distinct subgroup of germinal center B-cell-like diffuse large B-cell lymphoma

Daisuke Ennishi, Aixiang Jiang, Merrill Boyle, Brett Collinge, Bruno M. Grande, Susana Ben-Neriah, Christopher Rushton, Jeffrey Tang, Nicole Thomas, Graham W. Slack, Pedro Farinha, Katsuyoshi Takata, Tomoko Miyata-Takata, Jeffrey Craig, Anja Mottok, Barbara Meissner, Saeed Saberi, Ali Bashashati, Diego Villa, Kerry J. SavageLaurie H. Sehn, Robert Kridel, Andrew J. Mungall, Marco A. Marra, Sohrab P. Shah, Christian Steidl, Joseph M. Connors, Randy D. Gascoyne, Ryan D. Morin, David W. Scott

Research output: Contribution to journalArticlepeer-review

168 Citations (Scopus)


PURPOSE High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) has a poor outcome after standard chemoimmunotherapy. We sought to understand the biologic underpinnings of HGBL-DH/TH with BCL2 rearrangements (HGBL-DH/TH-BCL2) and diffuse large B-cell lymphoma (DLBCL) morphology through examination of gene expression. PATIENTS AND METHODS We analyzed RNA sequencing data from 157 de novo germinal center B-cell-like (GCB)-DLBCLs, including 25 with HGBL-DH/TH-BCL2, to define a gene expression signature that distinguishes HGBL-DH/TH-BCL2 from other GCB-DLBCLs. To assess the genetic, molecular, and phenotypic features associated with this signature, we analyzed targeted resequencing, whole-exome sequencing, RNA sequencing, and immunohistochemistry data. RESULTS We developed a 104-gene double-hit signature (DHITsig) that assigned 27% of GCB-DLBCLs to the DHITsig-positive group, with only one half harboring MYC and BCL2 rearrangements (HGBL-DH/TH-BCL2). DHITsig-positive patients had inferior outcomes after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy compared with DHITsig-negative patients (5-year time to progression rate, 57% and 81%, respectively; P, .001), irrespective of HGBL-DH/TH-BCL2 status. The prognostic value of DHITsig was confirmed in an independent validation cohort. DHITsig-positive tumors are biologically characterized by a putative non–light zone germinal center cell of origin and a distinct mutational landscape that comprises genes associated with chromatin modification. A new NanoString assay (DLBCL90) recapitulated the prognostic significance and RNA sequencing assignments. Validating the association with HGBL-DH/TH-BCL2, 11 of 25 DHITsig-positive–transformed follicular lymphomas were classified as HGBL-DH/ TH-BCL2 compared with zero of 50 in the DHITsig-negative group. Furthermore, the DHITsig was shared with the majority of B-cell lymphomas with high-grade morphology tested. CONCLUSION We have defined a clinically and biologically distinct subgroup of tumors within GCB-DLBCL characterized by a gene expression signature of HGBL-DH/TH-BCL2. This knowledge has been translated into an assay applicable to routinely available biopsy samples, which enables exploration of its utility to guide patient management.

Original languageEnglish
Pages (from-to)190-201
Number of pages12
JournalJournal of Clinical Oncology
Issue number3
Publication statusPublished - Jan 20 2019
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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