Double-Hit Gene Expression Signature Defines a Distinct Subgroup of Germinal Center B-Cell-Like Diffuse Large B-Cell...

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) exhibits poor prognosis with standard chemoimmunotherapy.
• Understanding the molecular basis of HGBL-DH/TH with BCL2 rearrangements (HGBL-DH/TH-BCL2) and diffuse large B-cell lymphoma (DLBCL) morphology is crucial for improving patient outcomes.

Purpose of the Study:

• To define a gene expression signature distinguishing HGBL-DH/TH-BCL2 from other germinal center B-cell-like (GCB)-DLBCLs.
• To investigate the genetic, molecular, and phenotypic features associated with this signature.
• To assess the clinical utility of this signature in predicting treatment response.

Main Methods:

• Analysis of RNA sequencing data from 157 de novo GCB-DLBCLs, including 25 HGBL-DH/TH-BCL2 cases.
• Development of a 104-gene double-hit signature (DHITsig) using gene expression profiling.
• Validation of the signature's prognostic value in an independent cohort and through a NanoString assay (DLBCL90).

Main Results:

• A 104-gene DHITsig identified 27% of GCB-DLBCLs as DHITsig-positive, with HGBL-DH/TH-BCL2 in half of these cases.
• DHITsig-positive patients showed significantly inferior outcomes after standard immunochemotherapy compared to DHITsig-negative patients (5-year progression-free survival: 57% vs. 81%, P < .001).
• DHITsig-positive tumors exhibited characteristics of non-light zone germinal center origin and a distinct mutational landscape involving chromatin modification genes. The signature was also found in HGBL-DH/TH-BCL2 transformed follicular lymphomas and other high-grade B-cell lymphomas.

Conclusions:

• A clinically and biologically distinct subgroup of GCB-DLBCL, characterized by the DHITsig, has been identified.
• The DHITsig has been translated into a practical assay for routine biopsy samples, potentially guiding patient management.
• This signature provides a novel tool for stratifying DLBCL patients and understanding disease biology.