Waldenstrom’s Macroglobulinemia (WM) is a rare, slow-growing cancer that originates in the white blood cells. This condition is classified as a type of non-Hodgkin lymphoma, specifically lymphoplasmacytic lymphoma (LPL). Understanding the cause of this disease is a common concern for patients and their families, especially regarding its potential appearance in relatives. Despite its rarity, specific genetic mechanisms have been identified that drive its development.
Understanding Waldenstrom’s Macroglobulinemia
WM is characterized by the uncontrolled growth of abnormal B cells, known as lymphoplasmacytic cells, primarily within the bone marrow. These cancerous cells share features of both lymphocytes and plasma cells. Their accumulation can crowd out healthy blood cells, leading to complications like anemia.
The defining feature of WM is the overproduction of the immunoglobulin M (IgM) protein, an antibody. The excess IgM protein causes hyperviscosity syndrome, a serious condition where the blood thickens and impedes flow. This thickening contributes to symptoms such as vision problems, headaches, and excessive bleeding.
Other common symptoms include chronic fatigue, weight loss, night sweats, and peripheral neuropathy (tingling in the hands or feet). Since WM is an indolent, slow-growing malignancy, many individuals may not experience symptoms for years, leading to a diagnosis during routine blood work.
Familial Predisposition and Hereditary Risk
WM is not classified as a purely hereditary disease, meaning it is not directly passed down from parent to child through a single, dominant gene. Instead, WM exhibits a notable familial predisposition, meaning the disease appears in multiple members of the same family far more often than would be expected by chance. This familial clustering suggests a shared genetic susceptibility or a combination of genetic and environmental factors are at play.
Studies show that first-degree relatives (parents, siblings, and children) of a WM patient have a significantly increased risk of developing WM, up to 20-fold compared to the general population. Relatives also show an elevated risk for other related B-cell malignancies, such as chronic lymphocytic leukemia, indicating a common inherited susceptibility to disorders of the immune system.
Somatic and Inherited Genetic Factors
Understanding the cause of WM requires distinguishing between two types of genetic changes: somatic and inherited (germline) mutations. Somatic mutations are acquired during a person’s lifetime in specific cells and are not passed on to children.
The primary somatic driver mutation in WM is MYD88 L265P, found in over 90% of WM cases. This acquired mutation activates signaling pathways, promoting the survival and growth of the malignant B-cells.
Another common somatic mutation is found in the CXCR4 gene, occurring in approximately 30% to 40% of WM patients, nearly always alongside the MYD88 mutation. The presence of CXCR4 mutations is associated with a different pattern of disease presentation, including a higher burden of disease in the bone marrow and a greater likelihood of hyperviscosity syndrome. These somatic changes are the direct cause of the cancer in the affected individual.
The hereditary component is attributed to germline variants, which are inherited changes present in all of an individual’s cells. Research has identified specific germline variants in genes involved in DNA repair and immune regulation that are enriched in familial cases of WM. This suggests that a person inherits a genetic susceptibility that, when combined with an acquired MYD88 L265P mutation or other somatic changes, increases the chance of developing WM.
Monitoring Relatives and Risk Management
Given the established familial risk, risk management involves monitoring unaffected family members of WM patients. This surveillance focuses on identifying a precursor condition called IgM Monoclonal Gammopathy of Undetermined Significance (IgM MGUS).
IgM MGUS is a state where an individual has the abnormal IgM protein in their blood but does not yet meet the diagnostic criteria for active WM. Studies show that first-degree relatives of WM patients are at a significantly increased risk of developing IgM MGUS compared to the general population.
While most people with IgM MGUS never progress to active WM, its detection is an important marker of genetic susceptibility. Monitoring typically involves regular blood tests, such as serum protein electrophoresis and IgM level measurement, to detect and track the monoclonal protein. Early detection allows for active monitoring and timely intervention if the condition progresses to symptomatic WM, providing a personalized approach to risk management.