A groundbreaking study has identified three distinct molecular subtypes of follicular lymphoma (FL), offering fresh insights that could revolutionize precision diagnostics and personalized treatment strategies for patients across Asia and the West. This pivotal research was collaboratively conducted by scientists at BGI Genomics’ Institute of Intelligent Medical Research (IIMR) and Sweden’s Karolinska Institutet, with findings published in Cell Reports Medicine in early August.
The research team employed whole-genome sequencing (WGS) on 131 Chinese patients, revealing the genetic landscape of FL. The study categorized the condition into three subtypes: C1, C2, and C3. These findings were further validated in an independent cohort of 227 Western patients, confirming the stability of these subtypes across different populations.
Understanding Follicular Lymphoma
Follicular lymphoma is a common type of non-Hodgkin lymphoma characterized by the abnormal growth of white blood cells within the lymph nodes, leading to the formation of clumps known as follicles. This disease is typically slow-growing and often diagnosed at advanced stages due to its subtle or absent symptoms. While some patients experience an indolent disease progression for years, others face rapid advancement 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 profiling through WGS is crucial for precision treatment.”
Mapping the Subtypes Through WGS
Using WGS on 131 tumor samples, researchers uncovered critical differences in mutation profiles, tumor microenvironments (TME), and clinical behavior. The samples were classified into three biologically and clinically meaningful subtypes:
The C2 Subtype
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 harbor high-risk mutations, necessitating better predictive measures for stronger treatment needs. Fortunately, these tumors often respond well to therapies targeting the BCL2 protein.
The C1 Subtype
The second subtype, C1, presents 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 sets C1 apart is its strong interaction with the immune system. These tumors are rich in immune cells and exhibit signs of inflammation, potentially making them more responsive to immunotherapies such as checkpoint inhibitors. Due to this immune activity, patients with C1 tend to have a better long-term outlook compared to other subtypes.
The C3 Subtype
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, more prevalent in Asia, was associated with a higher frequency of C1 and C3 subtypes. This may explain why FL behaves differently in Western versus Asian populations and underscores the need for population-specific diagnostic models.
Genetic Insights Driving 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, indicating a robust presence of fighting immune cells. The C2 subtype with a medium prognosis has moderate inflammatory signals due to a moderate number of immune cells. The C3 subtype has the worst prognosis as it is an “immune desert,” lacking almost any 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, while 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, tailoring 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.
