Double-Hit Lymphoma (DHL) is an aggressive and rare subtype of B-cell non-Hodgkin lymphoma, accounting for approximately five percent of Diffuse Large B-cell Lymphoma cases. The defining characteristic of DHL is the presence of specific genetic abnormalities within the cancerous B-cells. This condition is overwhelmingly caused by acquired, or somatic, genetic changes that occur over a person’s lifetime. Therefore, Double-Hit Lymphoma is generally not considered a hereditary disease passed down from parent to child.
The Defining Genetic Rearrangements of DHL
Double-Hit Lymphoma is biologically defined by chromosomal abnormalities known as translocations, which involve two or more specific genes. These translocations are classified as “hits” and involve the MYC gene and at least one other high-grade lymphoma-associated gene, most commonly BCL2 or BCL6. The most frequent combination involves translocations of both the MYC and BCL2 genes, though the MYC and BCL6 pairing also occurs. The presence of rearrangements in all three genes (MYC, BCL2, and BCL6) is referred to as triple-hit lymphoma.
These genes normally act as master regulators of B-cell function, controlling cell growth, division, and programmed cell death. The MYC gene, for instance, promotes cell multiplication and regulates approximately 15 percent of human genes. The BCL2 gene, in contrast, typically acts to inhibit apoptosis, which is the process of controlled cell death.
A translocation occurs when a piece of one chromosome breaks off and attaches to another. This rearrangement places the MYC and BCL2 (or BCL6) genes near highly active regulatory regions, causing them to be overexpressed. The resulting overproduction of the MYC protein drives rapid cell growth and division, while the overexpressed BCL2 protein prevents the cell from dying. This dual mechanism of uncontrolled proliferation and prolonged survival creates a highly aggressive cancer that characterizes Double-Hit Lymphoma.
Somatic Mutations: Why Double-Hit Lymphoma is Not Inherited
DHL is not hereditary due to the distinction between germline and somatic mutations. Germline mutations are inherited from a parent and are present in every cell of the body from conception. These are the changes that can be passed down to future generations.
In contrast, the genetic translocations that define DHL are somatic mutations, meaning they are acquired during a person’s lifetime. These changes occur only in the specific B-lymphocyte cells that eventually become cancerous, and they are not present in the germ cells (sperm or egg). Since the mutations are confined to the tumor cells, they cannot be transmitted to a person’s children. The vast majority of all cancers, including Double-Hit Lymphoma, are the result of these non-inherited, acquired somatic mutations.
These acquired genetic abnormalities often arise from random errors during cell division or from various environmental factors. The translocations happen in the B-cells as they mature in the germinal center of the lymph nodes. The specific process of rearranging immunoglobulin genes in B-cells can sometimes lead to accidental exchanges with other chromosomes, resulting in the MYC, BCL2, and BCL6 translocations.
The non-hereditary nature of the “double-hit” mechanism means offspring do not inherit the specific genetic blueprint for DHL. While a person may have a general genetic predisposition to cancer, the direct, cancer-causing translocations are unique to the individual’s tumor. This explains why the disease does not follow the predictable pattern of Mendelian inheritance seen in truly hereditary conditions.
Understanding Familial Lymphoma Risk and Predisposing Conditions
While the defining genetic changes of Double-Hit Lymphoma are not inherited, a person’s overall risk of developing lymphoma can be influenced by family history. This familial risk is typically small, but first-degree relatives of individuals with Non-Hodgkin Lymphoma (NHL) have an approximately 1.7-fold elevated risk compared to the general population. This slightly increased risk is thought to be due to shared small genetic changes, or variants, which individually have a minor effect but collectively increase susceptibility to lymphoma.
Familial risk can also be linked to rare, inherited genetic syndromes that impair immune function or DNA repair mechanisms. These germline conditions do not directly cause DHL but create a high-risk environment where B-cell lymphoma is more likely to develop. For example, the inherited disorder Ataxia-Telangiectasia, caused by a mutation in the ATM gene, affects DNA repair and increases the likelihood of developing lymphoma by approximately 2.6 times.
Mutations in genes like BRCA1 and BRCA2, known for their role in breast and ovarian cancer, have also been linked to an increased risk of lymphoma. Inheriting one of these high-risk syndromes is a germline event that increases the general probability of developing a lymphoid malignancy. If a lymphoma develops, it could potentially manifest as the aggressive Double-Hit subtype. However, the inherited genetic background only provides a predisposition; the actual transformation into DHL requires the accumulation of the specific somatic mutations in the B-cells.