It has been a prolific quarter for TFRI’s BC-based lymphoma research team. In the span of a few months, the team published two major papers in Blood, an important scientific journal that focuses on diseases of the blood. Both papers help to better understand diffuse large B-cell lymphoma (DLBCL), a heterogeneous form of non-Hodgkin lymphoma that has an average five-year relative survival rate of 64 per cent.
Should copy number alterations be used to further subtype double- and triple-hit lymphomas?
The first paper, published in April, focused on a subtype of DLBCL known as high-grade B-cell lymphoma with rearrangement of MYC and BCL2 and/or BCL6 (HGBL-DH/TH) – colloquially referred to as double- and triple-hit lymphoma. This subgroup of tumours is associated with a clinically aggressive disease course and poor patient outcomes.
The paper sought to answer if a proposed sub-classification of this disease based on copy number alterations (CNAs) is accurate. In the end, the team found that it was not.
“Using an assay that identifies a gene expression signature shared by HGBL-DH/TH tumours, this study demonstrates that tumours fulfilling this expanded definition do not share a similar underlying biology as HGBL-DH/TH, supporting the exclusion of CNAs from the diagnostic criteria of this clinical category,” says Brett Collinge, a graduate student at the University of British Columbia and the paper’s first author.
The finding is significant because properly identifying subgroups of patients with shared tumour biology using molecular diagnostics is the key to personalizing treatments for cancer patients.
“Better understanding the exact subtypes of the disease will ultimately enable more informative patient management and help guide the development of new treatment strategies,” says Collinge.
How to categorize DLBCLs that express a gene signature of mediastinal lymphomas?
The second paper, published in July, looked at lymphomas that were initially diagnosed as DLBCL but expressed a gene expression signature more akin to another type of lymphoma known as primary mediastinal large B-cell lymphoma (PMBL), which typically affects younger women. In this case, the team sought to understand if these lymphomas were ‘true PMBLs’ or if they represented a new subtype of DLBCL.
To answer this question, the team identified lymphomas with a PMBL signature from a cohort of 325 samples diagnosed as DLBCL and analyzed their clinical, mutational and immunophenotypic features. While the analysis allowed them to conclude that these tumours should remain in the DLBCL category, the team also found that the PMBL characteristics they display may make them more responsive to targeted therapies.
“Our study showed that these tumours are indeed clinically distinct from PMBL, and therefore should remain in the category of DLBCL. However, these tumours have PMBL-like molecular features that might make them treatable by molecularly targeted treatment, including existing immunotherapies that target PD1/PDL1,” say Gerben Duns and Elena Vigano, the paper’s shared first authors, adding that this finding could help personalize treatments for patients diagnosed with the newly discovered subtype of DLBCL.
The impact of MYC and BCL2 structural variants in tumors of DLBCL morphology and mechanisms of false-negative MYC IHC
Brett Collinge, Susana Ben-Neriah, Lauren Chong, Merrill Boyle, Aixiang Jiang, Tomoko Miyata-Takata, Pedro Farinha, Jeffrey W. Craig, Graham W. Slack, Daisuke Ennishi, Anja Mottok, Barbara Meissner, Elizabeth A. Chavez, Alina S. Gerrie, Diego Villa, Ciara Freeman, Kerry J. Savage, Laurie H. Sehn, Ryan D. Morin, Andrew J. Mungall, Randy D. Gascoyne, Marco A. Marra, Joseph M. Connors, Christian Steidl, and David W. Scott
Characterization of DLBCL with a PMBL gene expression signature
Gerben Duns, Elena Vigano, Daisuke Ennishi, Clementine Sarkozy, Stacy S. Hung, Elizabeth Chavez, Katsuyoshi Takata, Christopher Rushton, Aixiang Jiang, Susana Ben-Neriah, Bruce W. Woolcock, Graham W. Slack, Eric D. Hsi, Jeffrey W. Craig, Laura K. Hilton, Sohrab P. Shah, Pedro Farinha, Anja Mottok, Randy D. Gascoyne, Ryan D. Morin, Kerry J. Savage, David W. Scott, and Christian Steidl
This study was partly funded by the Terry Fox New Frontiers Program Project Grant in Overcoming treatment failure in lymphoid cancers