Hodgkin’s Lymphoma (HL), a cancer of the lymphatic system, originates when a lymphocyte undergoes an abnormal change in its DNA, leading to uncontrolled growth and the accumulation of cancerous cells. These abnormal cells, known as Hodgkin and Reed-Sternberg cells, typically form masses in the lymph nodes, though they can spread to other organs like the spleen and liver. While the exact cause remains unknown for most cases, researchers have identified various factors that contribute to the likelihood of its development. This article examines the influence of inherited factors on HL, distinguishing between direct genetic transmission and increased susceptibility.
Genetic Susceptibility vs. Direct Inheritance
HL is generally not classified as a strictly hereditary cancer, meaning it is rarely caused by a single gene mutation passed directly from parent to child, unlike certain BRCA-related cancers. Instead, the connection to family history is best described as familial clustering due to increased genetic susceptibility. A person may inherit a combination of common gene variations, or polygenic risk factors, that collectively make them more vulnerable when exposed to specific environmental triggers.
The risk is notably elevated for first-degree relatives (parents, siblings, or children). While the lifetime risk for the general population is low, first-degree relatives show an approximately threefold increased risk. The risk is highest for siblings, especially identical twins, who share the highest percentage of genetic material. Identical twins have a significantly higher rate of concordance compared to non-identical siblings, strongly suggesting a genetic component.
Research focuses on the Human Leukocyte Antigen (HLA) genes, which regulate the immune system’s response to foreign invaders. These genes, located on chromosome 6, are highly polymorphic (have many variations), and certain Class I and Class II HLA alleles are consistently associated with HL risk. Specific HLA types may predispose an individual by influencing how their immune system interacts with potential cancer-causing agents, such as viruses. For example, certain HLA-A and HLA-DR alleles are found more frequently in patients with HL, particularly those cases linked to the Epstein-Barr virus.
Primary Non-Hereditary Risk Factors
Since most HL cases are sporadic, acquired, non-hereditary factors influence risk. One significant association is with the Epstein-Barr Virus (EBV), which causes infectious mononucleosis (mono). EBV infects over 90% of the global population, and its DNA is found in the tumor cells of approximately 30% to 50% of classical HL cases. The virus is thought to contribute to cancer development by altering B-cells and helping them survive longer.
Another well-established risk is having a compromised immune system, due to an underlying medical condition or treatments. Individuals infected with HIV/AIDS have a substantially increased risk of developing HL, sometimes up to 11 times higher than the general population. Similarly, organ transplant recipients taking immunosuppressive medications show an increased incidence. Certain autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, are also linked to a modest increase in HL risk, likely due to chronic immune system activation.
Demographic factors also influence HL risk. The disease demonstrates a bimodal age distribution, most commonly diagnosed in two distinct age groups: young adults (20 to 30) and older adults (over 55). Additionally, males are slightly more likely to be diagnosed with HL than females. These patterns suggest that different combinations of genetic and environmental exposures may lead to the disease at different stages of life.
Interpreting Family History
For individuals with a family member diagnosed with HL, it is important to maintain perspective regarding the overall risk. Even with elevated relative risk due to familial clustering, the absolute lifetime risk for most first-degree relatives remains low because HL is an uncommon cancer. The presence of multiple affected relatives, especially siblings, should prompt a discussion with a healthcare provider to review the comprehensive family medical history.
Genetic counseling may be beneficial to understand familial risk, particularly if there are multiple cases of HL or other related lymphoid cancers. Currently, there is no standard screening test for HL for the general population or those with elevated familial risk. Therefore, awareness of potential symptoms is the most practical form of vigilance for individuals with a family history.
People should seek medical consultation if they experience persistent, unexplained swelling of lymph nodes (neck, armpit, or groin), the most common sign of the disease. They should also be aware of non-specific systemic symptoms known as “B symptoms,” including unexplained fever, drenching night sweats, or unexplained weight loss (10% or more of body weight over six months). Prompt reporting allows for early detection and diagnosis.