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Ed Forum 2018

Causes and Risk Factors


There is no definitely known cause of WM. As is the case with most cancers, there are probably multiple risk factors involved – some may be inherited predisposing genetic factors and some may be due to environmental or occupational exposures during one’s lifetime.


A risk factor is anything that increases the chances of developing a disease. The major risk factors that have been identified in WM include the following:

  • Male sex – the incidence of WM is significantly greater in men than in women.
  • Increasing age – the median age at diagnosis is approximately 65 years, although patients as young as 18 have been reported, and the annual incidence increases dramatically as age increases.
  • White race – the incidence is higher in whites than in blacks, but reliable figures for other races are not available.
  • IgM monoclonal gammopathy of undetermined significance (IgM MGUS) – refers to a condition in which the presence of a monoclonal IgM has been detected from blood tests, but there is no evidence of malignancy. In one long-term study of IgM MGUS, the incidence of progression to WM and other B-cell malignancies was 10% at 5 years, 18% at 10 years, and 24% at 15 years – a progression rate of approximately 1.5% each year.

Several reports have suggested a link between WM and certain genetic, environmental, and viral factors. It is highly likely that WM, as is true of most cancers, results from a combination of factors.

Researchers have determined that there is an element of familial susceptibility, meaning that in approximately 20% of WM patients there is a history of WM or related B-cell disorders (such as another non-Hodgkin’s lymphoma or chronic lymphocytic leukemia) in closely-related family members. The IWMF has been actively sponsoring research to discover genetic mutations in WM patients and determine their significance as risk factors for disease development and progression. Recent research has focused on mutations in genes called MYD88 and CXCR4.

A single mutation in the MYD88 gene initiates several downstream pathways that result in the expression of factors critical to the growth and proliferation of WM cells. This mutation is called MYD88 L265P, and it is found in more than 90% of WM patients. The presence of the mutation has value in establishing a diagnosis of WM, particularly in cases where the diagnosis is in question. It is likely that the mutation does not cause WM by itself, and researchers are still working to completely understand its significance to the development of the disease. Mutations in the CXCR4 gene occur at a prevalence rate of about 30% in WM. Studies suggest that CXCR4 mutations cause significant proliferation and spread to organs outside the bone marrow and may adversely impact response to certain treatments, especially BTK inhibitors such as ibrutinib (Imbruvica). For additional discussion about these genetic discoveries, see Future Directions.

Additional evidence links the disease to a deletion in part of chromosome 6, although this abnormality is not present in all cases of WM.

Environmental factors such as radiation exposure, Agent Orange exposure, and occupational exposure to leather, rubber, paints, dyes, wood dust, pesticides, and organic solvents have also been implicated, as have certain autoimmune diseases and viruses such as hepatitis C. However, the magnitude of risk from these exposures remains difficult to determine.

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