Integrating molecular approaches to advance the diagnostic and therapeutic framework of aggressive B-cell lymphomas
department or school: Medicine, Faculty of
department or school: Pathology and Laboratory Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Collinge, Brett
issued: 2025-10-27T16:59:00Z
issued: 2025
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Aggressive B-cell lymphomas encompass a heterogeneous group of neoplasms unified by their rapid clinical course and potential for cure with appropriate therapy. Traditional classification systems, grounded in morphology, often fail to capture the molecular diversity that shapes prognosis and therapeutic response. While molecular profiling has refined classification in diffuse large B-cell lymphoma (DLBCL), other entities remain poorly defined. Among these, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBCL-DH/TH) and high-grade B-cell lymphoma, not otherwise specified (HGBCL-NOS), represent challenging diagnostic groups with uncertain biological underpinnings. This thesis aimed to define the molecular landscape of HGBCL-DH/TH and HGBCL-NOS to refine their classification and support a biologically informed taxonomy of aggressive B-cell lymphomas. To achieve this, we assembled large study cohorts with detailed clinicopathological data and performed extensive molecular profiling. In HGBCL-DH/TH, tumors with MYC and BCL6 rearrangements exhibited marked heterogeneity, indicating that they do not constitute a single diagnostic group. In contrast, tumors with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) were biologically uniform and exhibited a characteristic gene expression signature. Molecular profiling demonstrated that in HGBCL-DH-BCL2, cooperative genetic alterations converge to dysregulate pathways active in dark zone germinal center B-cells, and that its characteristic gene expression signature closely aligns with transcriptomic profiles of dark zone B-cells. Expression of this signature, termed the dark zone signature (DZsig), extends beyond HGBCL-DH-BCL2 to identify a broader group of lymphomas unified by a dark zone phenotype, providing a biologically informed framework for classification and highlighting potential therapeutic vulnerabilities. Analysis of HGBCL-NOS confirmed that this category is not biologically cohesive but instead co…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/92729
note: INTEGRATING MOLECULAR APPROACHES TO ADVANCE THE DIAGNOSTIC AND THERAPEUTIC FRAMEWORK OF AGGRESSIVE B-CELL LYMPHOMAS by Brett Collinge A DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (PATHOLOGY AND LABORATORY MEDICINE) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) October 2025 © Brett Collinge, 2025 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Integrating Molecular Approaches to Advance the Diagnostic and Therapeutic Framework of Aggressive B-Cell Lymphomas submitted by Brett Collinge in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Pathology and Laboratory Medicine Examining Committee: David W. Scott, Professor, Department of Medicine, UBC Supervisor Christian Steidl, Professor, Department of Pathology and Laboratory Medicine, UBC Co-supervisor Stephen Yip, Associate Professor, Department of Pathology and Laboratory Medicine, UBC Supervisory committee member Brad Nelson, Professor, Department of Medical Genetics, UBC University Examiner Alexander Wyatt, Assistant Professor, Department of Urologic Sciences, UBC University Examiner Pierre Milpied, Director, Centre of Immunology of Marseille-Luminy, Aix-Marseille University External Examiner Additional Supervisory Committee Members: Martin Hirst, Professor, Department of Microbiology & Immunology, UBC Supervisory Committee Member Louis M. Staudt, Distinguished Investigator, Center for Cancer Research, National Cancer Institute Supervisory Committee Member iii Abstract Aggressive B-cell lymphomas encompass a heterogeneous group of neoplasms unified by their rapid clinical course and potential for cure with appropriate therapy. Traditional classification systems, grounded in morphology, often fail to capture the molecular diversity that shapes prognosis and…
has type: Thesis/Dissertation
date issued: 2026-05
is shown at: 10.14288/1.0450559
language: eng
degree discipline: Pathology and Laboratory Medicine
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Scott, David W.
contributor: Steidl, Christian
type: Text
identifier URI: http://hdl.handle.net/2429/92729