A new study has identified three distinct molecular subtypes of follicular lymphoma (FL), offering insights that may shape future precision diagnostics and personalized treatment plans for patients across Asia and the West.
The research was jointly conducted by scientists at BGI Genomics' Institute of Intelligent Medical Research (IIMR) and Sweden's Karolinska Institutet, published in Cell Reports Medicine early August.
The team applied whole-genome sequencing (WGS) to 131 Chinese patients, revealing FL's genetic landscape. The study classified the condition into three subtypes: C1, C2, and C3. These findings confirmed its stability across populations, through validation in an independent cohort of 227 Western patients.
Silent but Complex Disease
Follicular lymphoma, a common type of non-Hodgkin lymphoma. It will lead to abnormal growth of white blood cells within the lymph nodes, causing the formation of clumps called follicles.
Its typically slow-growing and often diagnosed at advanced stages due to its subtle or absent symptoms. While some patients experience indolent disease for years, others suffer from rapid progression and poor response to therapy.
"Understanding FL at the genomic level enables us to rethink treatment strategies," said Prof. Wu Kui, Chief Scientist and corresponding author from IIMR. "What appears clinically similar can be genetically distinct and lead to completely different treatment outcomes. Therefore, genetic profile through WGS is crucial for precision treatment."
WGS Mapping the Subtypes
Using WGS on 131 tumor samples, researchers uncovered critical differences in mutation profiles, tumor microenvironments (TME), and clinical behavior. The samples were ultimately classified into three biologically and clinically meaningful subtypes:
The most common form, classified as C2, accounts for about 80% of cases. This subtype usually grows slowly and is linked to a specific genetic change called BCL2-IGH, along with mutations in genes that control cell function, such as KMT2D, CREBBP, and EZH2. While many C2 cases are less aggressive, some can have high-risk mutations, meaning doctors need better ways to predict which patients may need stronger treatment. Fortunately, these tumors often respond well to therapies that target the BCL2 protein.
The second subtype, C1, has a different genetic profile—it lacks the typical BCL2-IGH change but instead has rearrangements in the BCL6 gene and mutations in genes like KLF2, NOTCH1/2, and TNFAIP3. What makes C1 unique is its strong interaction with the immune system. These tumors are filled with immune cells and show signs of inflammation, which might make them more responsive to immunotherapies like checkpoint inhibitors. Because of this immune activity, patients with C1 tend to have a better long-term outlook compared to other subtypes.
The third and most aggressive form is C3, which tends to grow quickly and often resists standard treatments. Many patients with C3 experience treatment failure within the first two years. This subtype has extensive genetic damage and may benefit from newer targeted drugs, such as BTK or PI3K inhibitors. Researchers have also identified a specific pattern of DNA damage linked to an enzyme called AID, which could help identify high-risk cases earlier.
The study also uncovered significant regional variations. Hepatitis B virus (HBV) infection, which is more common in Asia, was associated with a higher frequency of C1 and C3 subtypes. This may help explain why FL behaves differently in Western versus Asian populations and highlights the need for population-specific diagnostic models.
Genetics Guide Precision Treatment
The study found a clear correspondence between these three genetic subtypes and the tumor microenvironment. The C1 subtype with a good prognosis shows highly inflammatory infiltration inside the tumor, meaning that the tumor is full of fighting immune cells. The C2 subtype with a medium prognosis has moderate inflammatory signals because it has a moderate number of immune cells. The C3 subtype has the worst prognosis because it is an "immune desert," meaning it has almost no immune cells.
By leveraging WGS and deep molecular profiling, this study provides a blueprint for integrating genetic subtyping into routine FL diagnosis. It lays the foundation for personalized therapy: BCL2 and EZH2 inhibitors for C2, whereas C1 and C3 patients may benefit from PI3K inhibitors, IRF4 inhibitors, or BTK inhibitors.
Moreover, identifying AID-driven mutation patterns may allow clinicians to detect aggressive FL cases earlier, improving treatment decisions and outcomes.
"This study redefines our understanding of follicular lymphoma," said Prof. Wu. "Our findings bridge the gap between molecular biology and clinical treatment, bringing us closer to developing personalized treatment strategies for this complex disease."
The classification of follicular lymphoma into three distinct genomic subtypes opens new doors for precision oncology. As sequencing technologies become more accessible, the integration of WGS into standard clinical practice could transform the management of FL and tailor it not just to the disease, but to the patient's unique molecular profile.
About BGI Genomics
BGI Genomics , headquartered in Shenzhen, China, is the world's leading integrated solutions provider of precision medicine. Our services cover more than 100 countries and regions, involving more than 2,300 medical institutions. In July 2017, as a subsidiary of BGI Group, BGI Genomics (300676.SZ) was officially listed on the Shenzhen Stock Exchange.
