Ennishi D, et al. - Researchers aimed at clarifying the biologic underpinnings of high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) with BCL2 rearrangements (HGBL-DH/TH-BCL2) and diffuse large B-cell lymphoma (DLBCL) morphology through examination of gene expression. For this purpose, RNA sequencing data were analyzed 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. Within GCB-DLBCL, they defined a clinically and biologically distinct subgroup of tumors characterized by a gene expression signature of HGBL-DH/TH-BCL2. They translated this information into an assay that has applicability for routinely available biopsy samples, which enables exploration of its utility to guide patient management.

Methods

• Researchers defined a gene expression signature that distinguishes HGBL-DH/TH-BCL2 from other GCB-DLBCLs via analyzing RNA sequencing data from 157 de novo germinal center B-cell-like (GCB)-DLBCLs, including 25 with HGBL-DH/TH-BCL2.
• They determined the genetic, molecular, and phenotypic features associated with this signature, via analyzing targeted resequencing, whole-exome sequencing, RNA sequencing, and immunohistochemistry data.

Results

• A 104-gene double-hit signature (DHITsig) was developed; this signature assigned 27% of GCB-DLBCLs to the DHITsig-positive group, with only one half harboring MYC and BCL2 rearrangements (HGBL-DH/TH-BCL2).
• After rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy, DHITsig-positive patients displayed inferior outcomes compared with DHITsig-negative patients (5-year time to progression rate, 57% and 81%, respectively; P < .001), irrespective of HGBL-DH/TH-BCL2 status.
• Researchers verified the prognostic value of DHITsig in an independent validation cohort.
• A putative non–light zone germinal center cell of origin and a distinct mutational landscape that comprises genes associated with chromatin modification characterized DHITsig-positive tumors biologically.
• The prognostic significance and RNA sequencing assignments were recapitulated with a new NanoString assay (DLBCL90).
• Classification of 11 of 25 DHITsig-positive–transformed follicular lymphomas as HGBL-DH/TH-BCL2 compared with zero of 50 in the DHITsig-negative group was made, validating the association with HGBL-DH/TH-BCL2.
• Moreover, the majority of B-cell lymphomas with high-grade morphology tested shared the DHITsig.