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 journalArticle

28 Citations (Scopus)

Abstract

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
Volume37
Issue number3
DOIs
Publication statusPublished - Jan 20 2019
Externally publishedYes

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Germinal Center
Lymphoma, Large B-Cell, Diffuse
Transcriptome
RNA Sequence Analysis
B-Lymphocytes
B-Cell Lymphoma
Exome
Follicular Lymphoma
Vincristine
Prednisone
Non-Hodgkin's Lymphoma
Doxorubicin
Cyclophosphamide
Genes
Chromatin
Molecular Biology
Neoplasms
Immunohistochemistry
Biopsy
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Double-hit gene expression signature defines a distinct subgroup of germinal center B-cell-like diffuse large B-cell lymphoma. / Ennishi, Daisuke; Jiang, Aixiang; Boyle, Merrill; Collinge, Brett; Grande, Bruno M.; Ben-Neriah, Susana; Rushton, Christopher; Tang, Jeffrey; Thomas, Nicole; Slack, Graham W.; Farinha, Pedro; Takata, Katsuyoshi; Miyata-Takata, Tomoko; Craig, Jeffrey; Mottok, Anja; Meissner, Barbara; Saberi, Saeed; Bashashati, Ali; Villa, Diego; Savage, Kerry J.; Sehn, Laurie H.; Kridel, Robert; Mungall, Andrew J.; Marra, Marco A.; Shah, Sohrab P.; Steidl, Christian; Connors, Joseph M.; Gascoyne, Randy D.; Morin, Ryan D.; Scott, David W.

In: Journal of Clinical Oncology, Vol. 37, No. 3, 20.01.2019, p. 190-201.

Research output: Contribution to journalArticle

Ennishi, D, Jiang, A, Boyle, M, Collinge, B, Grande, BM, Ben-Neriah, S, Rushton, C, Tang, J, Thomas, N, Slack, GW, Farinha, P, Takata, K, Miyata-Takata, T, Craig, J, Mottok, A, Meissner, B, Saberi, S, Bashashati, A, Villa, D, Savage, KJ, Sehn, LH, Kridel, R, Mungall, AJ, Marra, MA, Shah, SP, Steidl, C, Connors, JM, Gascoyne, RD, Morin, RD & Scott, DW 2019, 'Double-hit gene expression signature defines a distinct subgroup of germinal center B-cell-like diffuse large B-cell lymphoma', Journal of Clinical Oncology, vol. 37, no. 3, pp. 190-201. https://doi.org/10.1200/JCO.18.01583
Ennishi, Daisuke ; Jiang, Aixiang ; Boyle, Merrill ; Collinge, Brett ; Grande, Bruno M. ; Ben-Neriah, Susana ; Rushton, Christopher ; Tang, Jeffrey ; Thomas, Nicole ; Slack, Graham W. ; Farinha, Pedro ; Takata, Katsuyoshi ; Miyata-Takata, Tomoko ; Craig, Jeffrey ; Mottok, Anja ; Meissner, Barbara ; Saberi, Saeed ; Bashashati, Ali ; Villa, Diego ; Savage, Kerry J. ; Sehn, Laurie H. ; Kridel, Robert ; Mungall, Andrew J. ; Marra, Marco A. ; Shah, Sohrab P. ; Steidl, Christian ; Connors, Joseph M. ; Gascoyne, Randy D. ; Morin, Ryan D. ; Scott, David W. / Double-hit gene expression signature defines a distinct subgroup of germinal center B-cell-like diffuse large B-cell lymphoma. In: Journal of Clinical Oncology. 2019 ; Vol. 37, No. 3. pp. 190-201.
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abstract = "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.",
author = "Daisuke Ennishi and Aixiang Jiang and Merrill Boyle and Brett Collinge and Grande, {Bruno M.} and Susana Ben-Neriah and Christopher Rushton and Jeffrey Tang and Nicole Thomas and Slack, {Graham W.} and Pedro Farinha and Katsuyoshi Takata and Tomoko Miyata-Takata and Jeffrey Craig and Anja Mottok and Barbara Meissner and Saeed Saberi and Ali Bashashati and Diego Villa and Savage, {Kerry J.} and Sehn, {Laurie H.} and Robert Kridel and Mungall, {Andrew J.} and Marra, {Marco A.} and Shah, {Sohrab P.} and Christian Steidl and Connors, {Joseph M.} and Gascoyne, {Randy D.} and Morin, {Ryan D.} and Scott, {David W.}",
year = "2019",
month = "1",
day = "20",
doi = "10.1200/JCO.18.01583",
language = "English",
volume = "37",
pages = "190--201",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
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TY - JOUR

T1 - Double-hit gene expression signature defines a distinct subgroup of germinal center B-cell-like diffuse large B-cell lymphoma

AU - Ennishi, Daisuke

AU - Jiang, Aixiang

AU - Boyle, Merrill

AU - Collinge, Brett

AU - Grande, Bruno M.

AU - Ben-Neriah, Susana

AU - Rushton, Christopher

AU - Tang, Jeffrey

AU - Thomas, Nicole

AU - Slack, Graham W.

AU - Farinha, Pedro

AU - Takata, Katsuyoshi

AU - Miyata-Takata, Tomoko

AU - Craig, Jeffrey

AU - Mottok, Anja

AU - Meissner, Barbara

AU - Saberi, Saeed

AU - Bashashati, Ali

AU - Villa, Diego

AU - Savage, Kerry J.

AU - Sehn, Laurie H.

AU - Kridel, Robert

AU - Mungall, Andrew J.

AU - Marra, Marco A.

AU - Shah, Sohrab P.

AU - Steidl, Christian

AU - Connors, Joseph M.

AU - Gascoyne, Randy D.

AU - Morin, Ryan D.

AU - Scott, David W.

PY - 2019/1/20

Y1 - 2019/1/20

N2 - 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.

AB - 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.

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