Genetic profiling of MYC and BCL2 in diffuse large B-cell lymphoma determines cell-of-origin-specific clinical impact

Daisuke Ennishi, Anja Mottok, Susana Ben-Neriah, Hennady P. Shulha, Pedro Farinha, Fong Chun Chan, Barbara Meissner, Merrill Boyle, Christoffer Hother, Robert Kridel, Daniel Lai, Saeed Saberi, Ali Bashashati, Sohrab P. Shah, Ryan D. Morin, Marco A. Marra, Kerry J. Savage, Laurie H. Sehn, Christian Steidl, Joseph M. ConnorsRandy D. Gascoyne, David W. Scott

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

The clinical significance of MYC and BCL2 genetic alterations in diffuse large B-cell lymphoma (DLBCL), apart from translocations, has not been comprehensively investigated using high-resolution genetic assays. In this study, we profiled MYC and BCL2 genetic alterations using next-generation sequencing and high-resolution SNP array in 347 de novo DLBCL cases treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) at the British Columbia Cancer Agency. Cell-oforigin (COO) subtype was determined by Lymph2Cx digital gene expression profiling. We showed that the incidence ofMYC/BCL2 genetic alterations and their clinical significance were largely dependent on COO subtypes. It is noteworthy that the presence of BCL2 gain/amplification is significantly associated with poor outcome in activated B-cell-like and BCL2 translocation with poor outcome in germinal center B-cell subtypes, respectively. Both have prognostic significance independent of MYC/BCL2 dual expression and the International Prognostic Index (IPI). Furthermore, the combination of BCL2 genetic alterations with IPI identifies markedly worse prognostic groups within individual COO subtypes. Thus, high-resolution genomic assays identify extremely poor prognostic groups within each COO subtype on the basis of BCL2 genetic status in this large, uniformly R-CHOP-treated population-based cohort of DLBCL. These results suggest COO subtype-specific biomarkers based on BCL2 genetic alterations can be used to risk-stratify patients with DLBCL treated with immunochemotherapy.

Original languageEnglish
Pages (from-to)2760-2770
Number of pages11
JournalBlood
Volume129
Issue number20
DOIs
Publication statusPublished - May 18 2017
Externally publishedYes

Fingerprint

Lymphoma, Large B-Cell, Diffuse
Cells
Assays
Vincristine
Biomarkers
Prednisone
Gene expression
B-Lymphocytes
Doxorubicin
Cyclophosphamide
Amplification
British Columbia
Germinal Center
Gene Expression Profiling
Single Nucleotide Polymorphism
Incidence
Population
Neoplasms

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Ennishi, D., Mottok, A., Ben-Neriah, S., Shulha, H. P., Farinha, P., Chan, F. C., ... Scott, D. W. (2017). Genetic profiling of MYC and BCL2 in diffuse large B-cell lymphoma determines cell-of-origin-specific clinical impact. Blood, 129(20), 2760-2770. https://doi.org/10.1182/blood-2016-11-747022

Genetic profiling of MYC and BCL2 in diffuse large B-cell lymphoma determines cell-of-origin-specific clinical impact. / Ennishi, Daisuke; Mottok, Anja; Ben-Neriah, Susana; Shulha, Hennady P.; Farinha, Pedro; Chan, Fong Chun; Meissner, Barbara; Boyle, Merrill; Hother, Christoffer; Kridel, Robert; Lai, Daniel; Saberi, Saeed; Bashashati, Ali; Shah, Sohrab P.; Morin, Ryan D.; Marra, Marco A.; Savage, Kerry J.; Sehn, Laurie H.; Steidl, Christian; Connors, Joseph M.; Gascoyne, Randy D.; Scott, David W.

In: Blood, Vol. 129, No. 20, 18.05.2017, p. 2760-2770.

Research output: Contribution to journalArticle

Ennishi, D, Mottok, A, Ben-Neriah, S, Shulha, HP, Farinha, P, Chan, FC, Meissner, B, Boyle, M, Hother, C, Kridel, R, Lai, D, Saberi, S, Bashashati, A, Shah, SP, Morin, RD, Marra, MA, Savage, KJ, Sehn, LH, Steidl, C, Connors, JM, Gascoyne, RD & Scott, DW 2017, 'Genetic profiling of MYC and BCL2 in diffuse large B-cell lymphoma determines cell-of-origin-specific clinical impact', Blood, vol. 129, no. 20, pp. 2760-2770. https://doi.org/10.1182/blood-2016-11-747022
Ennishi, Daisuke ; Mottok, Anja ; Ben-Neriah, Susana ; Shulha, Hennady P. ; Farinha, Pedro ; Chan, Fong Chun ; Meissner, Barbara ; Boyle, Merrill ; Hother, Christoffer ; Kridel, Robert ; Lai, Daniel ; Saberi, Saeed ; Bashashati, Ali ; Shah, Sohrab P. ; Morin, Ryan D. ; Marra, Marco A. ; Savage, Kerry J. ; Sehn, Laurie H. ; Steidl, Christian ; Connors, Joseph M. ; Gascoyne, Randy D. ; Scott, David W. / Genetic profiling of MYC and BCL2 in diffuse large B-cell lymphoma determines cell-of-origin-specific clinical impact. In: Blood. 2017 ; Vol. 129, No. 20. pp. 2760-2770.
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abstract = "The clinical significance of MYC and BCL2 genetic alterations in diffuse large B-cell lymphoma (DLBCL), apart from translocations, has not been comprehensively investigated using high-resolution genetic assays. In this study, we profiled MYC and BCL2 genetic alterations using next-generation sequencing and high-resolution SNP array in 347 de novo DLBCL cases treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) at the British Columbia Cancer Agency. Cell-oforigin (COO) subtype was determined by Lymph2Cx digital gene expression profiling. We showed that the incidence ofMYC/BCL2 genetic alterations and their clinical significance were largely dependent on COO subtypes. It is noteworthy that the presence of BCL2 gain/amplification is significantly associated with poor outcome in activated B-cell-like and BCL2 translocation with poor outcome in germinal center B-cell subtypes, respectively. Both have prognostic significance independent of MYC/BCL2 dual expression and the International Prognostic Index (IPI). Furthermore, the combination of BCL2 genetic alterations with IPI identifies markedly worse prognostic groups within individual COO subtypes. Thus, high-resolution genomic assays identify extremely poor prognostic groups within each COO subtype on the basis of BCL2 genetic status in this large, uniformly R-CHOP-treated population-based cohort of DLBCL. These results suggest COO subtype-specific biomarkers based on BCL2 genetic alterations can be used to risk-stratify patients with DLBCL treated with immunochemotherapy.",
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AU - Ennishi, Daisuke

AU - Mottok, Anja

AU - Ben-Neriah, Susana

AU - Shulha, Hennady P.

AU - Farinha, Pedro

AU - Chan, Fong Chun

AU - Meissner, Barbara

AU - Boyle, Merrill

AU - Hother, Christoffer

AU - Kridel, Robert

AU - Lai, Daniel

AU - Saberi, Saeed

AU - Bashashati, Ali

AU - Shah, Sohrab P.

AU - Morin, Ryan D.

AU - Marra, Marco A.

AU - Savage, Kerry J.

AU - Sehn, Laurie H.

AU - Steidl, Christian

AU - Connors, Joseph M.

AU - Gascoyne, Randy D.

AU - Scott, David W.

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N2 - The clinical significance of MYC and BCL2 genetic alterations in diffuse large B-cell lymphoma (DLBCL), apart from translocations, has not been comprehensively investigated using high-resolution genetic assays. In this study, we profiled MYC and BCL2 genetic alterations using next-generation sequencing and high-resolution SNP array in 347 de novo DLBCL cases treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) at the British Columbia Cancer Agency. Cell-oforigin (COO) subtype was determined by Lymph2Cx digital gene expression profiling. We showed that the incidence ofMYC/BCL2 genetic alterations and their clinical significance were largely dependent on COO subtypes. It is noteworthy that the presence of BCL2 gain/amplification is significantly associated with poor outcome in activated B-cell-like and BCL2 translocation with poor outcome in germinal center B-cell subtypes, respectively. Both have prognostic significance independent of MYC/BCL2 dual expression and the International Prognostic Index (IPI). Furthermore, the combination of BCL2 genetic alterations with IPI identifies markedly worse prognostic groups within individual COO subtypes. Thus, high-resolution genomic assays identify extremely poor prognostic groups within each COO subtype on the basis of BCL2 genetic status in this large, uniformly R-CHOP-treated population-based cohort of DLBCL. These results suggest COO subtype-specific biomarkers based on BCL2 genetic alterations can be used to risk-stratify patients with DLBCL treated with immunochemotherapy.

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