A groundbreaking study led by researchers at BGI Genomics’ Institute of Intelligent Medical Research (IIMR) in collaboration with Sweden’s Karolinska Institutet has unveiled three distinct molecular subtypes of follicular lymphoma (FL), a common form of non-Hodgkin lymphoma. This discovery, published in the prestigious journal Cell Reports Medicine, marks a significant leap forward in the precision medicine landscape, promising to revolutionize diagnostic accuracy and tailored treatment strategies for FL patients worldwide, especially across diverse populations in Asia and the West.
Follicular lymphoma is characterized by the abnormal proliferation of white blood cells within lymph nodes, resulting in follicle-like structures. Despite being one of the more indolent lymphomas, FL presents a clinical paradox: some patients endure a slow-progressing disease over years, while others experience rapid deterioration and poor therapeutic response. This heterogeneity has long challenged oncologists, often leading to a one-size-fits-all approach in treatment. The new genomic insights offered by whole-genome sequencing (WGS) herald a new era where the biological underpinnings dictate therapy.
By employing WGS on tumor samples from 131 Chinese patients, the research team meticulously charted the genetic landscape of follicular lymphoma, culminating in the identification of three biologically and clinically significant subtypes: C1, C2, and C3. To ensure the robustness and universality of these findings, the subtypes were validated against an independent cohort of 227 Western patients, confirming the stability of these molecular patterns across ethnicities and geographic boundaries.
Subtype C2 emerged as the predominant form, accounting for approximately 80% of cases studied. Genetically, C2 is marked by the hallmark BCL2-IGH chromosomal translocation, which leads to overexpression of the anti-apoptotic BCL2 protein, fostering tumor cell survival. Complementing this genetic hallmark are mutations in epigenetic regulators such as KMT2D, CREBBP, and EZH2, which collectively orchestrate aberrant transcriptional landscapes. Clinically, C2 tumors exhibit moderate aggressiveness but often respond favorably to targeted therapies, particularly BCL2 inhibitors, emphasizing the therapeutic promise encoded in this subtype’s precise genomic makeup.
In sharp contrast, the C1 subtype lacks the canonical BCL2-IGH rearrangement but displays alternative genetic alterations, including BCL6 gene rearrangements and mutations in genes such as KLF2, NOTCH1/2, and TNFAIP3. What sets C1 apart is its robust immune microenvironment characterized by dense immune cell infiltration and heightened inflammatory signaling. This immunogenic milieu not only shapes tumor biology but hints at superior responsiveness to emerging immunotherapeutic agents, including immune checkpoint inhibitors. Remarkably, patients harboring C1 tumors generally exhibit better prognoses, underscoring the clinical significance of tumor-immune interactions in FL.
The third subtype, C3, paints a much grimmer clinical picture. Tumors in this group demonstrate extensive genomic instability and a high mutational burden driven by aberrant activity of the enzyme Activation-Induced cytidine Deaminase (AID), which is known to induce DNA damage. C3’s tumor microenvironment starkly contrasts with C1, depicting an “immune desert” devoid of significant immune infiltration. Clinically, this results in aggressive disease progression and frequent treatment failures within the first two years post-diagnosis. However, this understanding opens new therapeutic avenues, suggesting that patients with C3 tumors might benefit from cutting-edge targeted treatments such as BTK or PI3K inhibitors that interrupt critical signaling pathways.
A fascinating regional nuance uncovered by the study is the influence of hepatitis B virus (HBV) infection, prevalent in Asia, on subtype distribution. HBV-positive individuals were more likely to develop the C1 and C3 subtypes, suggesting viral infection may shape lymphoma pathogenesis and contribute to observed disparities in clinical outcomes between Eastern and Western populations. This finding accentuates the need to incorporate population-specific factors into precision oncology models, tailoring approaches not only to molecular subtypes but also to geographic and epidemiologic contexts.
The integration of comprehensive WGS data with deep phenotyping of the tumor microenvironment (TME) revealed a striking correlation between genetic subtypes and immune landscapes. The C1 subtype, marked by extensive immune infiltration and inflammation, corresponds to favorable clinical outcomes, while C2 exhibits intermediate immune engagement. Conversely, immune evasion characterizes the poor-prognosis C3 subtype, emphasizing the profound interplay between tumor genome and host immunity. This tripartite classification provides an invaluable framework for clinicians to align therapeutic strategies with tumor biology.
Importantly, the study underscores the clinical utility of WGS as a diagnostic gold standard that transcends traditional histopathological classifications. By capturing the full spectrum of genomic alterations and their functional consequences, WGS equips clinicians with actionable intelligence to personalize therapy. For instance, patients with C2 tumors might prioritize BCL2 and EZH2 inhibitors, whereas those with C1 or C3 subtypes could benefit more from immunomodulatory or kinase-inhibitor therapies such as PI3K, IRF4, or BTK antagonists.
Beyond therapy selection, the identification of AID-associated mutational signatures in aggressive FL cases introduces a novel biomarker for early risk stratification. Detecting these mutation patterns could enable timely clinical interventions, potentially transforming prognosis and survival rates for patients otherwise facing rapid disease progression. This finding exemplifies how molecular diagnostics can usher in proactive, rather than reactive, treatment paradigms.
Professor Wu Kui, Chief Scientist at IIMR and the study’s corresponding author, elaborated on the transformative impact of these findings: “Our research redefines follicular lymphoma beyond a monolithic disease entity. By elucidating the distinct genetic and immunological landscapes within FL, we bridge the gap between molecular biology and clinical practice, paving the way for truly personalized medicine.”
The deployment of this three-subtype genomic framework heralds a new chapter in FL management, laying the groundwork for integrating WGS into routine clinical workflows globally. As sequencing technologies become increasingly affordable and accessible, the vision of precision oncology tailored to each patient’s unique molecular fingerprint moves closer to reality. This paradigm shift promises not only better clinical outcomes but also optimized use of healthcare resources by sparing patients from ineffective treatments.
BGI Genomics, headquartered in Shenzhen, China, exemplifies the vanguard of this revolution. As a global leader in precision medicine, their commitment to integrating advanced genomics with clinical insights across more than 100 countries exemplifies the future of healthcare. The company’s strategic partnership with esteemed institutions like Karolinska Institutet further accelerates molecular discoveries with real-world impact.
In conclusion, the classification of follicular lymphoma into three clearly delineated molecular subtypes represents a milestone in cancer genomics and precision oncology. This research not only enhances our biological understanding of FL but also charts a pragmatic course for individualized patient care, harnessing genetics to unlock new therapeutic frontiers. As this knowledge permeates clinical practice, the hope is that FL patients worldwide will benefit from more effective, less toxic, and personalized treatment options, fundamentally changing the disease trajectory.
Subject of Research: Follicular Lymphoma Molecular Subtyping and Precision Oncology
Article Title: Three Distinct Genomic Subtypes of Follicular Lymphoma Unveiled by Whole-Genome Sequencing
News Publication Date: August 2025
Web References:
DOI: 10.1016/j.xcrm.2025.102278
Image Credits: BGI Genomics
Keywords: Follicular lymphoma, Non-Hodgkin lymphoma, Whole-genome sequencing, Molecular subtypes, BCL2-IGH translocation, Tumor microenvironment, Cancer genomics, Precision medicine, Immunotherapy, Epigenetic mutations, Hepatitis B virus, Targeted therapy
