BC Cancer Study Uncovers Biological Diversity and New Subtypes in Hodgkin Lymphoma

Classic Hodgkin lymphoma (CHL), a subtype of Hodgkin lymphoma (HL)—a cancer originating in the lymphatic system—has long been recognized for its high cure rates, often exceeding 80% with standard chemotherapy and radiation. However, for the subset of patients who relapse or do not respond to initial treatments, outcomes remain challenging. A groundbreaking study from BC Cancer researchers is reshaping our understanding of this disease by revealing its underlying biological diversity and identifying distinct subtypes that could pave the way for precision medicine approaches tailored to individual patients.

What Is Classic Hodgkin Lymphoma and Why Does Subtype Discovery Matter?

Hodgkin lymphoma, first described by British physician Thomas Hodgkin in 1832, is characterized by the presence of large, abnormal cells known as Reed-Sternberg cells within lymph nodes. These multinucleated giant cells, derived from B-lymphocytes, create a unique tumor microenvironment rich in immune cells that paradoxically supports cancer growth rather than fighting it. CHL accounts for about 95% of all HL cases and is histologically classified into four traditional subtypes: nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted. Despite these morphological distinctions, treatment has historically been uniform, primarily involving regimens like ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine) combined with radiation for early stages.

In Canada, HL is relatively rare, with approximately 1,000 new cases diagnosed annually nationwide. In British Columbia specifically, projections for 2025 estimate around 135 new cases, split roughly evenly between genders. While overall five-year survival rates hover at 88% for adults, relapsed or refractory cases drop to 50-65%, underscoring the need for better risk stratification and targeted therapies. The new BC Cancer study challenges the one-size-fits-all paradigm by demonstrating that CHL harbors significant biological heterogeneity, driven by genetic mutations, tumor-immune interactions, and microenvironmental differences.

The BC Cancer Study: A Multidimensional Breakthrough

Led by clinician-scientist Dr. Tomohiro Aoki, formerly a postdoctoral fellow at BC Cancer and now at Princess Margaret Cancer Centre, with principal investigator Dr. Christian Steidl—executive director of research at BC Cancer and professor of pathology and laboratory medicine at the University of British Columbia (UBC)—the study was published in the prestigious journal *Cancer Discovery* on January 30, 2026. Titled "Multidimensional Characterization of Tumor–Immune Architecture Reveals Clinically Relevant Classic Hodgkin Lymphoma Subtypes," it integrates advanced techniques to map the complex ecosystem within CHL tumors.

The research team analyzed tumor samples from a large cohort of patients, employing genetic sequencing, molecular profiling, and high-resolution imaging to dissect cancer cells' interactions with surrounding immune cells. This holistic approach uncovered four novel molecular subtypes under a new classification system called HLGen: CST, CN913, STB, and CN2P. Each subtype exhibits unique mutational profiles, gene expression patterns, and immune landscapes, correlating with distinct clinical behaviors such as progression risk and therapy response.

Deep Dive into the Four CHL Subtypes

The HLGen subtypes represent a paradigm shift, moving beyond histology to biology. Here's a breakdown:

• CST Subtype: Defined by genetic alterations that trigger the release of thymus and activation-regulated chemokine (TARC), fostering an immunosuppressive environment. This subtype evades immune surveillance, potentially explaining poorer responses to immunotherapy in affected patients.
• CN913 Subtype: Features specific copy number variations (CN) and genetic mutations, associated with aggressive tumor growth and altered immune cell infiltration patterns.
• STB Subtype: Characterized by stromal and T-cell biology signatures, indicating robust stromal support for cancer cells and heightened T-cell activity that may influence prognosis.
• CN2P Subtype: Marked by distinct copy number changes and proliferation markers, correlating with higher proliferation rates and potential sensitivity to certain chemotherapies.

These distinctions enable precise subtype assignment via biopsy analysis, guiding therapy selection—for instance, immune checkpoint inhibitors like nivolumab for less suppressive subtypes.

Advanced Methods Powering the Discovery

The study's rigor stems from multidimensional profiling: whole-genome sequencing captured somatic mutations, while spatial transcriptomics visualized cellular neighborhoods within tumors. Computational algorithms clustered samples into subtypes based on integrated data layers, validated against clinical outcomes like event-free survival. This methodology, honed at the BC Cancer Research Centre (BCCRC), exemplifies cutting-edge bioinformatics in oncology.

Funding from the Terry Fox Research Institute, Canadian Cancer Society, and Genome BC supported this work, highlighting Canada's leadership in genomic medicine.

Clinical Implications and Precision Medicine Potential

Subtype-aware treatment could boost outcomes. For example, CST patients might benefit from TARC-targeted agents or combination immunotherapies to dismantle suppression. Early data suggest subtype-specific progression risks, with STB potentially faring better under standard regimens. This aligns with global shifts toward biomarker-driven care, as seen in other lymphomas.Learn more from BC Cancer.

In Canada, where universal healthcare facilitates trial access, these findings could accelerate adoption. BC Cancer's lymphoid cancer center already pioneers such innovations.

UBC and Higher Education's Role in Cancer Research

Dr. Steidl's dual role at BC Cancer and UBC underscores academia's pivotal contribution. UBC's Faculty of Medicine trains next-generation oncologists, with programs emphasizing translational research. This study emerged from collaborative PhD and postdoc training, fostering expertise in multi-omics.Explore research jobs in Canadian universities drive such advances.

Higher education institutions like UBC host specialized labs, attracting global talent. For aspiring researchers, opportunities abound in pathology, genomics, and immunology—fields central to this discovery. Craft your academic CV to join these efforts.

Epidemiology and Impact in Canada

HL peaks in young adults (15-39 years), with incidence stable but survival improving due to research. In 2025, Canada's projected cases: ~1,000, with BC's 135 reflecting its population share. Risk factors include EBV infection, family history, and immunosuppression. Indigenous and rural populations face disparities in access, addressed by BC Cancer's provincial network.BC Cancer HL overview.

• Age-standardized incidence: ~2.5 per 100,000.
• 5-year survival: 88% overall, 95% early-stage.
• Relapse rate: 10-30%.

Stakeholder Perspectives and Expert Insights

"This work challenges the traditional view of Hodgkin lymphoma as one uniform disease," says Dr. Steidl. Dr. Aoki adds, "By defining biologically meaningful subtypes, we can better match treatments to specific subtypes." Lymphoma Canada praises the study for empowering patients through knowledge.

Challenges include assay standardization for HLGen and trial design for rare subtypes. Solutions: pan-Canadian registries and AI-driven diagnostics.

Future Outlook: Trials, Careers, and Global Influence

Upcoming trials at BC Cancer will test subtype-guided therapies. The 2024 Karl Musshoff Prize at ISHL signals international acclaim. For higher ed, this boosts demand for clinical research jobs and postdoc positions.

Students and professors eyeing oncology should note UBC's ecosystem. University jobs in Canada offer stability amid global talent wars.

Actionable Insights for Researchers and Patients

• Discuss subtype testing with oncologists.
• Participate in trials via BC Cancer trials.
• Academics: Collaborate on HLGen validation.

This study exemplifies how university-led research transforms lives. Explore higher ed jobs, career advice, and professor ratings to advance in academia. In British Columbia and across Canada, innovation thrives.

Photo by Noble Mitchell on Unsplash