A gene expression signature originally described as being characteristic for high-grade double-hit B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) also identifies dark zone lymphomas, according to research published in Blood.

This signature, renamed DZsig, identifies patients within germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) with inferior outcomes and shorter time to treatment.

Researchers examined the prevalence and outcomes of molecular subgroups in a real-world population of 1149 unselected patients with de novo DLBCL. Patient’s biopsy samples were assessed using fluorescence in situ hybridization (FISH), immunohistochemistry, and digital gene expression profiling. This allowed the researchers to assign cell-of-origin and the “double-hit signature” to the tumors.

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They study showed the double-hit signature was expressed in 21% of GCB-DLBCL cases (n=431) and in all Burkitt lymphomas examined (n=55). The team renamed the double-hit signature the “dark zone signature” (DZsig) to reflect this latter finding.

Among subtypes, 2-year overall survival was 57% in DZsig-positive DLBCL, 89% in non-DZsig positive GCB-DLBCL, and 71% in activated B-cell-like (ABC)-DLBCL. The FISH analysis found 62% of DZsig-positive tumors were negative for HGBCL-DH-BCL2, but these DZsig-positive tumors were associated with outcomes similar to those in HGBCL-DH-BCL2 tumors.

Compared to those with GCB-DLBCL, patients with DZsig-positive and ABC-DLBCL had a shorter diagnosis-to-treatment interval (DTI ratio, 0.79; 95% CI, 0.65-0.96; P <.01 for DZsig-positive) and DTI was associated with both OS and freedom from progression among patients treated with R-CHOP.

“DZsig expression extends beyond HGBCL-DH-BCL2 and captures a poor-prognosis DLBCL subgroup with short DTI, including patients unidentifiable by routine FISH testing, that should be considered for treatment intensification or novel therapies in prospective trials,” the researchers concluded in their report.

The primary limitations of the study included the retrospective design, exclusion of patients with insufficient remaining tissue or only bone/BM-derived biopsies, which was were found to have had worse outcomes and shorter DTI than patients with evaluable biopsies, and small sample sizes in some survival comparisons.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of authors’ disclosures. 


Alduaij W, Collinge B, Ben-Neriah S, et al. Molecular determinants of clinical outcomes in a real-world diffuse large B-cell lymphoma population. Blood. 2023;141(20):2493-2507. doi:10.1182/blood.2022018248