Diffuse large B cell lymphoma (DLBCL) does not have a single cause. It develops when B cells, a type of white blood cell central to your immune system, acquire genetic changes that allow them to grow uncontrollably. What triggers those changes varies from person to person, but researchers have identified several overlapping factors: accumulated genetic mutations, immune system dysfunction, viral infections, chronic inflammation, family history, and certain environmental exposures. DLBCL is the most common type of non-Hodgkin lymphoma, diagnosed at a rate of about 5.6 per 100,000 people per year in the United States, with a median age at diagnosis of 67.
Genetic Mutations That Drive the Disease
At the cellular level, DLBCL is fundamentally a disease of broken genetic instructions. B cells normally grow, divide, and eventually die on a tightly regulated schedule. When key genes controlling that schedule are damaged or rearranged, cells can start dividing without stopping and resist the normal signals telling them to self-destruct.
The most common genetic change in DLBCL involves genes that control how DNA is packaged and read. Mutations in these “chromatin modifier” genes appear in roughly 85% of cases. The single most frequently mutated gene, KMT2D, is altered in about 30% of all DLBCL tumors. Another gene called CREBBP is mutated in about 25%. These mutations effectively scramble the cell’s ability to turn tumor-suppressing programs on and off.
Chromosomal translocations, where chunks of DNA break off and reattach in the wrong place, also play a major role. Three genes are most commonly affected: BCL2, BCL6, and MYC. When these genes get fused next to the wrong regulatory sequence, they become permanently switched on, pushing the cell to keep dividing or to avoid programmed cell death. BCL6, for instance, is disrupted by translocations in about 35% of cases and by point mutations in 75%.
DLBCL comes in two main molecular subtypes, and each carries a distinct genetic fingerprint. The germinal center B cell (GCB) subtype tends to have mutations that silence anti-growth genes. The activated B cell (ABC) subtype is instead characterized by mutations that keep an inflammatory signaling pathway called NF-κB permanently turned on. In ABC-DLBCL, roughly 30% of cases carry a specific mutation in MYD88, and another 30% have mutations in a gene called TNFAIP3 that normally acts as a brake on inflammation. About 25% of ABC cases also lose a gene called PRDM1, which blocks the B cell from maturing normally, essentially freezing it in a rapidly dividing state.
Immune System Suppression
A healthy immune system does more than fight infections. It also surveils the body for abnormal cells and destroys them before they can form tumors. When that surveillance system is weakened, the risk of DLBCL rises significantly.
Organ transplant recipients face some of the highest risk. Because they take immunosuppressive drugs to prevent organ rejection, their immune systems are less able to detect and eliminate rogue B cells. A CDC-linked study found that solid organ transplant recipients developed DLBCL at 12.6 times the rate of the general population. The risk was highest in the first year after transplantation, particularly among patients who were not previously exposed to Epstein-Barr virus (EBV) and those who received potent immune-suppressing treatments at the time of surgery.
HIV infection also substantially raises DLBCL risk by depleting the immune cells that would normally keep B cell growth in check. Before effective antiretroviral therapy became widespread, lymphoma was one of the most common cancers among people with HIV. Modern treatment has reduced but not eliminated this elevated risk.
The Role of Epstein-Barr Virus
Epstein-Barr virus, the virus behind mononucleosis, infects the vast majority of adults worldwide and then lies dormant in B cells for life. In most people it never causes problems. But in a subset of DLBCL cases, EBV appears to actively contribute to cancer development.
EBV-positive DLBCL is now recognized as its own distinct category. Interestingly, these tumors carry fewer of the chromosomal rearrangements (like BCL2 and MYC translocations) seen in typical DLBCL, suggesting the virus itself provides an alternative push toward uncontrolled growth. EBV promotes tumor development in part by reshaping the environment around the tumor, suppressing the local immune response so cancer cells can grow unchecked. This subtype is more common in older adults and in people with weakened immune systems, where the body’s ability to keep the dormant virus in check is reduced.
Autoimmune Disease and Chronic Inflammation
Autoimmune diseases force the immune system into a state of constant activation, and that chronic stimulation of B cells creates more opportunities for cancer-causing mutations to accumulate. The connection between autoimmune conditions and DLBCL is well documented.
In a large analysis of over 4,600 DLBCL cases, autoimmune diseases that specifically activate B cells were associated with a 2.4-fold increased risk of DLBCL. Sjögren syndrome and systemic lupus erythematosus (lupus) showed the strongest associations. Sjögren syndrome in particular has long been linked to lymphoma, carrying between 4 and 40 times the general population risk of non-Hodgkin lymphoma overall.
Rheumatoid arthritis also carries risk, and the degree of risk appears tied to how active the inflammation is. A Swedish study of more than 74,000 rheumatoid arthritis patients found that those with greater inflammatory activity had a higher likelihood of developing DLBCL specifically. The mechanism makes intuitive sense: the same processes that drive autoimmune disease, namely constant B cell stimulation by the body’s own proteins, also represent the conditions under which lymphoma can take root.
Family History and Inherited Risk
DLBCL is not inherited in the way that some cancers with single-gene mutations are, but having a close relative with lymphoma does increase your risk. The largest pooled study on the topic, involving more than 17,000 non-Hodgkin lymphoma cases, found that people with a first-degree relative (parent, sibling, or child) who had non-Hodgkin lymphoma faced a 1.8-fold increased risk of DLBCL. A family history of Hodgkin lymphoma raised DLBCL risk by about 2.1-fold.
One of the more striking findings from registry-based studies is how tightly risk clusters by subtype. First-degree relatives of someone with DLBCL had a 9.8-fold increased risk of developing DLBCL themselves, but they were not at increased risk of follicular lymphoma, a closely related but distinct type. This suggests that whatever inherited genetic susceptibility is involved, it is specific to the biology of DLBCL rather than a general predisposition to all lymphomas.
Environmental and Chemical Exposures
Certain occupational and environmental exposures have been linked to higher rates of DLBCL, though these associations are generally weaker than the genetic and immune-related factors. The most consistent evidence involves agricultural chemicals. A systematic review coordinated by the International Agency for Research on Cancer found a positive association between DLBCL and occupational exposure to phenoxy herbicides, a class of weed-killing chemicals used widely in farming.
Industrial solvents, particularly certain organic chemicals, have also been studied as possible contributors, though the evidence for specific compounds is less definitive. For most people, chemical exposure alone is unlikely to cause DLBCL, but it may add incremental risk on top of other predisposing factors.
Why Most Cases Have No Single Explanation
Men develop DLBCL at a higher rate than women (6.6 versus 4.6 per 100,000), and incidence rises steadily with age. But the majority of people diagnosed have no obvious risk factor they can point to. They don’t have HIV, they haven’t had a transplant, and they have no family history of lymphoma. In these cases, the disease most likely results from the gradual accumulation of random genetic errors in B cells over a lifetime, compounded by age-related decline in immune surveillance. Each division of a B cell carries a small chance of a copying error, and over decades, the wrong combination of errors in the wrong cell can set the disease in motion.
This is why DLBCL clusters in older adults. It is not that aging causes lymphoma directly, but that more time means more opportunities for the specific genetic mistakes that underlie it. The known risk factors, including immune suppression, viral infection, chronic inflammation, and chemical exposure, essentially accelerate or add to that baseline accumulation of damage.