Scientists have identified a genetic defect that may explain why some individuals develop Kaposi sarcoma without apparent immune deficiencies, potentially paving the way for more targeted treatments.

A new study has uncovered a hidden genetic cause that could help explain why certain people develop Kaposi sarcoma despite having no known immunodeficiency. The research, published in the Journal of Allergy and Clinical Immunology, identifies RIG-I deficiency as a key factor contributing to this rare cancer caused by human herpesvirus 8 (HHV-8).

The study, conducted at the Research Institute of the McGill University Health Center, focused on a patient of Inuit origin who was diagnosed with Kaposi sarcoma at age 72. This case raised questions about how someone without apparent immune problems could develop this typically immunosuppressive disease.

Using whole-exome sequencing, researchers pinpointed a mutation in the DDX58 gene responsible for preventing the expression of the RIG-I protein. The team then developed experimental systems using the patient's cells to track infection and assess their ability to detect and fight the virus. These experiments revealed that the cells responded abnormally, allowing the virus to persist and promote cancer development.

"This genetic defect doesn't just weaken the immune response—it directly changes how the virus behaves," explains Dr. Don Vinh, senior author of the study. "In the absence of RIG-I, the virus is able to hide within cells and drive their transformation into cancerous cells."

The discovery challenges longstanding assumptions about RIG-I's role in antiviral defense. Previously known for detecting RNA viruses like those causing influenza or COVID-19, this study shows that RIG-I also plays a critical role in defending against Kaposi sarcoma-associated herpesvirus (KSHV), which is a DNA virus.

"This finding opens new avenues for treatment and research," Dr. Vinh notes. "It may support the use of genetic testing to identify patients at risk, improve treatments with interferon-based therapies, and better understand why these diseases are more common in certain populations."

The study highlights the importance of understanding underlying mechanisms in cancer development, particularly those involving viral infections. By identifying RIG-I deficiency as a potential cause of Kaposi sarcoma, researchers pave the way for more targeted and potentially more effective treatments.

This breakthrough underscores the critical role of genetic research in advancing our understanding of complex diseases like Kaposi sarcoma. As more is learned about these mechanisms, it may lead to improved diagnostic tools and personalized treatment strategies for affected individuals.