McGill University's Groundbreaking Discovery in Kaposi's Sarcoma Research

Researchers at McGill University have made a pivotal advancement in understanding Kaposi's sarcoma, a rare but aggressive cancer linked to human herpesvirus 8 (HHV-8, also known as Kaposi sarcoma-associated herpesvirus or KSHV). This breakthrough identifies the first documented human case of retinoic acid-inducible gene I (RIG-I) deficiency as a direct cause of classic Kaposi's sarcoma in an otherwise healthy individual, opening new avenues for diagnosis and therapy.

The study, led by Dr. Donald C. Vinh from the Research Institute of the McGill University Health Centre (RI-MUHC), challenges long-standing assumptions about the disease. Traditionally associated with severe immunosuppression like HIV or organ transplants, classic Kaposi's sarcoma occurs sporadically in immunocompetent people, particularly older adults or those from specific ethnic groups such as Mediterranean, Middle Eastern, Eastern European, or Inuit communities. McGill's work reveals a hidden genetic culprit: a mutation in the DDX58 gene that abolishes RIG-I protein expression.

RIG-I, encoded by DDX58, is a crucial sensor in the innate immune system, previously known primarily for detecting RNA viruses like influenza or SARS-CoV-2. This research expands its role to DNA viruses, showing how its absence allows HHV-8 to evade detection, persist latently, and reprogram cells into cancerous ones. Conducted within McGill's Infectious Diseases and Immunity in Global Health Program, the findings were published in the Journal of Allergy and Clinical Immunology (DOI: 10.1016/j.jaci.2026.02.027).

What is Kaposi's Sarcoma and Why Does It Matter in Canada?

Kaposi's sarcoma manifests as violaceous nodules or plaques on the skin, mucous membranes, or internal organs, arising from endothelial cells lining blood and lymph vessels. Caused exclusively by HHV-8 infection, it requires immune dysfunction for progression, but classic forms puzzle scientists because patients show no overt immunodeficiency.

In Canada, sarcomas overall have an incidence of about 44 cases per million annually, with Kaposi's sarcoma representing a small but notable subset, particularly among HIV-positive individuals pre-ART era. Incidence has declined dramatically with antiretroviral therapy—from 132 to 43 cases per 100,000 person-years among males with HIV from 2009-2019—but sporadic classic cases persist, especially in aging populations or high-risk ethnic groups like Inuit communities. McGill's proximity to diverse populations in Quebec positions it ideally for such studies.

This rarity underscores the importance of university-led research hubs like RI-MUHC, where basic science intersects clinical care to address underserved diseases.

McGill's Legacy in Cancer and Viral Research

McGill University, one of Canada's premier research institutions, boasts a storied history in oncology and virology. The Mark Wainberg Centre for Viral Diseases exemplifies this, focusing on HIV-associated cancers like Kaposi's sarcoma in treated patients. RI-MUHC, McGill's flagship research arm, integrates genomics, immunology, and clinical trials, supported by funding from CIHR and partners—recently $7.9 million for cancer prevention alone.

Dr. Vinh's team builds on this, using whole-exome sequencing and custom cell models. McGill's interdisciplinary approach—spanning medicine, human genetics, and microbiology—fosters breakthroughs, training next-gen researchers through graduate programs and attracting global talent.

The Patient Case: A Catalyst for Discovery

The index patient, a 72-year-old Inuit man, presented at MUHC with violaceous nodules on his feet and lower legs—hallmarks of KS. HIV-negative with normal immune markers, his case defied norms, prompting genetic scrutiny.

Whole-exome sequencing revealed a homozygous nonsense mutation (p.Q393*) in DDX58, eliminating RIG-I. Patient-derived cells infected with fluorescent KSHV showed poor viral clearance, persistent latency, and oncogenic reprogramming, confirming causality.

Decoding RIG-I: From RNA to DNA Virus Sentinel

RIG-I typically recognizes viral RNA, triggering type I interferons (IFN-α/β) and antiviral states. McGill experiments demonstrated RIG-I also curbs HHV-8 by preventing latency—a dormant state where viral genes reprogram host cells without lysis.

Without RIG-I, KSHV evades detection, skews interferon-stimulated genes, and activates pro-cancer pathways. Transcriptomics and proteomics validated this, highlighting RIG-I's expanded antiviral portfolio.

Innovative Methods Powering the Breakthrough

• Genetic Analysis: Whole-exome sequencing identified DDX58 mutation.
• Functional Assays: Isogenic cell lines (patient vs. corrected) tracked real-time KSHV infection.
• Multi-Omics: RNA-seq and proteomics profiled interferon deficits and oncogenesis.
• Viral Models: Fluorescent KSHV quantified primary infection and reactivation.

These tools, honed at McGill's core facilities, exemplify advanced higher ed research infrastructure.

Key Findings: Latency Loss and Oncogenic Shift

Core results: RIG-I loss impairs IFN induction, favors latent KSHV genes, dysregulates cell survival pathways. This 'first innate immunodeficiency for classic KS' redefines pathogenesis, suggesting genetic screening for KS patients.

Treatment Horizons: Precision from Genetics

Current KS therapies—chemotherapy, radiation—are blunt. McGill's insight points to RIG-I agonists or targeted IFNs like beta/omega, potentially more effective with fewer side effects than IFN-α. For more, see the full study at Journal of Allergy and Clinical Immunology.

Genetic testing could stratify patients, enhancing outcomes in Canada's universal healthcare.

McGill's Role in Canadian Higher Ed Research Ecosystem

As Canada's top-ranked medical doctoral university, McGill invests heavily in translational research. RI-MUHC's programs train PhD/MD students in genomics-immunity interfaces, contributing to national priorities like rare diseases via RARE-Qc.

This KS work exemplifies how federal funding (CIHR) and partnerships amplify impact, positioning Canadian unis as global leaders.

Expert Insights and Dr. Vinh's Vision

"By studying a single patient in depth, we identified a hidden genetic cause," says Dr. Vinh. "This defect changes how the virus behaves, promoting cancer." Future: Probe other sensors, population genetics for screening.

Future Outlook: Transforming KS Care at McGill and Beyond

McGill plans expanded genetic cohorts, clinical trials for IFN therapies. In higher ed, this boosts interdisciplinary training, attracting talent amid Canada's research renaissance (5th globally). Details at MUHC announcement.

This positions McGill—and Canadian universities—as vital in precision oncology.

Photo by Michael Starkie on Unsplash