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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. Connors, Randy D. Gascoyne and David W. Scott

Key points

  • MYC and BCL2 genetic alterations are associated with COO subtype-specific clinical impact in R-CHOP treated DLBCL.

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-of-Origin (COO) subtype was determined by Lymph2Cx digital gene expression profiling. We showed that the incidence of MYC/BCL2 genetic alterations and their clinical significance were largely dependent on COO subtypes. Noteworthy, the presence of BCL2 gain/amplification is significantly associated with poor outcome in Activated B-Cell-like (ABC) and BCL2 translocation with poor outcome in Germinal Centre B-cell (GCB) 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 DLBCL patients treated with immunochemotherapy.

  • Submitted November 4, 2016.
  • Accepted March 17, 2017.