Double-Hit Gene Expression Signature Defines a Distinct Subgroup of Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma
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...
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| Vydáno v: | Journal of clinical oncology Ročník 37; číslo 3; s. 190 |
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| Hlavní autoři: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
United States
20.01.2019
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| Témata: | |
| ISSN: | 1527-7755, 1527-7755 |
| On-line přístup: | Zjistit podrobnosti o přístupu |
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| Abstract | 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.
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.
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.
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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| AbstractList | 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.PURPOSEHigh-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.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.PATIENTS AND METHODSWe 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.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.RESULTSWe 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.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.CONCLUSIONWe 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. 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. 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. 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. 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 | Slack, Graham W Jiang, Aixiang Takata, Katsuyoshi Ennishi, Daisuke Sehn, Laurie H Tang, Jeffrey Morin, Ryan D Craig, Jeffrey Savage, Kerry J Kridel, Robert Marra, Marco A Mungall, Andrew J Bashashati, Ali Thomas, Nicole Collinge, Brett Gascoyne, Randy D Boyle, Merrill Rushton, Christopher Mottok, Anja Meissner, Barbara Villa, Diego Farinha, Pedro Saberi, Saeed Miyata-Takata, Tomoko Steidl, Christian Shah, Sohrab P Scott, David W Ben-Neriah, Susana Connors, Joseph M Grande, Bruno M |
| Author_xml | – sequence: 1 givenname: Daisuke surname: Ennishi fullname: Ennishi, Daisuke organization: 1 British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, British Columbia, Canada – sequence: 2 givenname: Aixiang surname: Jiang fullname: Jiang, Aixiang organization: 2 Simon Fraser University, Burnaby, British Columbia, Canada – sequence: 3 givenname: Merrill surname: Boyle fullname: Boyle, Merrill organization: 1 British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, British Columbia, Canada – sequence: 4 givenname: Brett surname: Collinge fullname: Collinge, Brett organization: 1 British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, British Columbia, Canada – sequence: 5 givenname: Bruno M surname: Grande fullname: Grande, Bruno M organization: 2 Simon Fraser University, Burnaby, British Columbia, Canada – sequence: 6 givenname: Susana surname: Ben-Neriah fullname: Ben-Neriah, Susana organization: 1 British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, British Columbia, Canada – sequence: 7 givenname: Christopher surname: Rushton fullname: Rushton, Christopher organization: 2 Simon Fraser University, Burnaby, British Columbia, Canada – sequence: 8 givenname: Jeffrey surname: Tang fullname: Tang, Jeffrey organization: 2 Simon Fraser University, Burnaby, British Columbia, Canada – sequence: 9 givenname: Nicole surname: Thomas fullname: Thomas, Nicole organization: 2 Simon Fraser University, Burnaby, British Columbia, Canada – sequence: 10 givenname: Graham W surname: Slack fullname: Slack, Graham W organization: 1 British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, British Columbia, Canada – sequence: 11 givenname: Pedro surname: Farinha fullname: Farinha, Pedro organization: 1 British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, British Columbia, Canada – sequence: 12 givenname: Katsuyoshi surname: Takata fullname: Takata, Katsuyoshi organization: 1 British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, British Columbia, Canada – sequence: 13 givenname: Tomoko surname: Miyata-Takata fullname: Miyata-Takata, Tomoko organization: 1 British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, British Columbia, Canada – sequence: 14 givenname: Jeffrey surname: Craig fullname: Craig, Jeffrey organization: 1 British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, British Columbia, Canada – sequence: 15 givenname: Anja surname: Mottok fullname: Mottok, Anja organization: 3 Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany – sequence: 16 givenname: Barbara surname: Meissner fullname: Meissner, Barbara organization: 1 British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, British Columbia, Canada – sequence: 17 givenname: Saeed surname: Saberi fullname: Saberi, Saeed organization: 4 Molecular Oncology, British Columbia Cancer, Vancouver, British Columbia, Canada – sequence: 18 givenname: Ali surname: Bashashati fullname: Bashashati, Ali organization: 4 Molecular Oncology, British Columbia Cancer, Vancouver, British Columbia, Canada – sequence: 19 givenname: Diego surname: Villa fullname: Villa, Diego organization: 1 British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, British Columbia, Canada – sequence: 20 givenname: Kerry J surname: Savage fullname: Savage, Kerry J organization: 1 British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, British Columbia, Canada – sequence: 21 givenname: Laurie H surname: Sehn fullname: Sehn, Laurie H organization: 1 British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, British Columbia, Canada – sequence: 22 givenname: Robert surname: Kridel fullname: Kridel, Robert organization: 5 Princess Margaret Cancer Center-University Health Network, Toronto, Ontario, Canada – sequence: 23 givenname: Andrew J surname: Mungall fullname: Mungall, Andrew J organization: 6 Genome Sciences Center, British Columbia Cancer Agency, Vancouver, British Columbia, Canada – sequence: 24 givenname: Marco A surname: Marra fullname: Marra, Marco A organization: 6 Genome Sciences Center, British Columbia Cancer Agency, Vancouver, British Columbia, Canada – sequence: 25 givenname: Sohrab P surname: Shah fullname: Shah, Sohrab P organization: 4 Molecular Oncology, British Columbia Cancer, Vancouver, British Columbia, Canada – sequence: 26 givenname: Christian surname: Steidl fullname: Steidl, Christian organization: 1 British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, British Columbia, Canada – sequence: 27 givenname: Joseph M surname: Connors fullname: Connors, Joseph M organization: 1 British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, British Columbia, Canada – sequence: 28 givenname: Randy D surname: Gascoyne fullname: Gascoyne, Randy D organization: 1 British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, British Columbia, Canada – sequence: 29 givenname: Ryan D surname: Morin fullname: Morin, Ryan D organization: 2 Simon Fraser University, Burnaby, British Columbia, Canada – sequence: 30 givenname: David W surname: Scott fullname: Scott, David W organization: 1 British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, British Columbia, Canada |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30523716$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | Adult Aged Aged, 80 and over Antibodies, Monoclonal, Murine-Derived - administration & dosage Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - therapeutic use Cyclophosphamide - administration & dosage Doxorubicin - administration & dosage Female Gene Rearrangement Germinal Center - pathology Humans Lymphoma, B-Cell - drug therapy Lymphoma, B-Cell - genetics Lymphoma, B-Cell - pathology Lymphoma, Large B-Cell, Diffuse - drug therapy Lymphoma, Large B-Cell, Diffuse - genetics Lymphoma, Large B-Cell, Diffuse - pathology Male Middle Aged Prednisone - administration & dosage Prognosis Proto-Oncogene Proteins c-bcl-2 - genetics Proto-Oncogene Proteins c-myc - genetics Rituximab - administration & dosage RNA, Neoplasm - genetics Transcriptome Vincristine - administration & dosage Young Adult |
| Title | Double-Hit Gene Expression Signature Defines a Distinct Subgroup of Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma |
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