PMID- 36302166 OWN - NLM STAT- MEDLINE DCOM- 20230522 LR - 20230627 IS - 1528-0020 (Electronic) IS - 0006-4971 (Linking) VI - 141 IP - 20 DP - 2023 May 18 TI - Molecular determinants of clinical outcomes in a real-world diffuse large B-cell lymphoma population. PG - 2493-2507 LID - 10.1182/blood.2022018248 [doi] AB - Molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) underlies the variable outcomes achieved with immunochemotherapy. However, outcomes of gene expression profiling (GEP)-defined molecular subgroups in a real-world DLBCL population remain unknown. Here we examined the prevalence and outcomes of molecular subgroups in an unselected population of 1149 patients with de novo DLBCL in British Columbia, Canada. Evaluable biopsies were profiled by fluorescence in situ hybridization (FISH), immunohistochemistry, and digital GEP to assign cell-of-origin and the so-called "double-hit signature" (DHITsig)-a signature originally described as being characteristic for high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2). DHITsig was expressed in 21% of 431 germinal center B-cell-like (GCB)-DLBCL and all 55 Burkitt lymphomas examined. Reflecting this latter finding, DHITsig has been renamed the "dark zone signature" (DZsig). DZsigpos-DLBCL, non-DZsigpos GCB-DLBCL and activated B-cell-like (ABC)-DLBCL were associated with a 2 year overall survival of 57%, 89%, and 71%, respectively. 62% of DZsigpos tumors were negative for HGBCL-DH-BCL2 by FISH, but were associated with outcomes similar to HGBCL-DH-BCL2. A small group of HGBCL-DH-BCL2 that lacked DZsig expression had different molecular features compared with DZsig-expressing HGBCL-DH-BCL2 and were associated with favorable outcomes comparable to DLBCL, not otherwise specified. DZsigpos and ABC-DLBCL had a shorter diagnosis-to-treatment interval (DTI) than GCB-DLBCL, with this metric being associated with outcome. In conclusion, 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. CI - (c) 2023 by The American Society of Hematology. FAU - Alduaij, Waleed AU - Alduaij W AUID- ORCID: 0000-0002-2365-5371 AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. AD - UBC Clinician Investigator Program, The University of British Columbia, Vancouver, BC, Canada. FAU - Collinge, Brett AU - Collinge B AUID- ORCID: 0000-0002-5860-2798 AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. AD - Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada. FAU - Ben-Neriah, Susana AU - Ben-Neriah S AUID- ORCID: 0000-0002-2867-4037 AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Jiang, Aixiang AU - Jiang A AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. AD - Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada. FAU - Hilton, Laura K AU - Hilton LK AUID- ORCID: 0000-0002-6413-6586 AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Boyle, Merrill AU - Boyle M AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Meissner, Barbara AU - Meissner B AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Chong, Lauren AU - Chong L AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Miyata-Takata, Tomoko AU - Miyata-Takata T AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Slack, Graham W AU - Slack GW AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. AD - Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada. FAU - Farinha, Pedro AU - Farinha P AUID- ORCID: 0000-0001-9364-9391 AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. AD - Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada. FAU - Craig, Jeffrey W AU - Craig JW AUID- ORCID: 0000-0003-1295-3258 AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. AD - Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada. FAU - Lytle, Andrew AU - Lytle A AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. AD - Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada. FAU - Savage, Kerry J AU - Savage KJ AUID- ORCID: 0000-0002-5835-9863 AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. AD - Division of Medical Oncology, Department of Medicine, The University of British Columbia, Vancouver, BC, Canada. FAU - Villa, Diego AU - Villa D AUID- ORCID: 0000-0002-4625-3009 AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. AD - Division of Medical Oncology, Department of Medicine, The University of British Columbia, Vancouver, BC, Canada. FAU - Gerrie, Alina S AU - Gerrie AS AUID- ORCID: 0000-0003-4727-1425 AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. AD - Division of Medical Oncology, Department of Medicine, The University of British Columbia, Vancouver, BC, Canada. FAU - Freeman, Ciara L AU - Freeman CL AUID- ORCID: 0000-0002-0662-6480 AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. AD - Division of Medical Oncology, Department of Medicine, The University of British Columbia, Vancouver, BC, Canada. FAU - Gascoyne, Randy D AU - Gascoyne RD AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Connors, Joseph M AU - Connors JM AUID- ORCID: 0000-0002-1361-7531 AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Morin, Ryan D AU - Morin RD AUID- ORCID: 0000-0003-2932-7800 AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. AD - Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada. AD - Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada. FAU - Sehn, Laurie H AU - Sehn LH AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. AD - Division of Medical Oncology, Department of Medicine, The University of British Columbia, Vancouver, BC, Canada. FAU - Mungall, Andrew J AU - Mungall AJ AUID- ORCID: 0000-0002-0905-2742 AD - Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada. FAU - Steidl, Christian AU - Steidl C AUID- ORCID: 0000-0001-9842-9750 AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. AD - Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada. FAU - Scott, David W AU - Scott DW AUID- ORCID: 0000-0002-0435-5947 AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. AD - Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada. AD - Division of Medical Oncology, Department of Medicine, The University of British Columbia, Vancouver, BC, Canada. LA - eng GR - GPH-129347/CIHR/Canada GR - GPI-155873/CIHR/Canada GR - 300738/CIHR/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (Proto-Oncogene Proteins c-myc) RN - 0 (Proto-Oncogene Proteins c-bcl-2) SB - IM CIN - Blood. 2023 May 18;141(20):2413-2415. PMID: 37200058 MH - Humans MH - In Situ Hybridization, Fluorescence MH - Prospective Studies MH - *Proto-Oncogene Proteins c-myc/genetics MH - Proto-Oncogene Proteins c-bcl-2/genetics/metabolism MH - *Lymphoma, Large B-Cell, Diffuse/drug therapy/epidemiology/genetics MH - Prognosis EDAT- 2022/10/28 06:00 MHDA- 2023/05/22 06:42 CRDT- 2022/10/27 15:02 PHST- 2022/10/12 00:00 [accepted] PHST- 2022/08/29 00:00 [received] PHST- 2023/05/22 06:42 [medline] PHST- 2022/10/28 06:00 [pubmed] PHST- 2022/10/27 15:02 [entrez] AID - S0006-4971(22)07885-5 [pii] AID - 10.1182/blood.2022018248 [doi] PST - ppublish SO - Blood. 2023 May 18;141(20):2493-2507. doi: 10.1182/blood.2022018248.