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

Research paper by Daisuke D Ennishi, Anja A Mottok, Susana S Ben-Neriah, Hennady P HP Shulha, Pedro P Farinha, Fong Chun FC Chan, Barbara B Meissner, Merrill M Boyle, Christoffer C Hother, Robert R Kridel, Daniel D Lai, Saeed S Saberi, Ali A Bashashati, Sohrab P SP Shah, Ryan D RD Morin, et al.

Indexed on: 30 Mar '17Published on: 30 Mar '17Published in: Blood



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.

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