In a study recently published in the journal Science, researchers Bert Vogelstein and Christian Tomasetti at Johns Hopkins University sought to explain why some tissues give rise to human cancers more often than others. Using existing data, the researchers found that the lifetime risk of cancer was strongly correlated with increased numbers of stem cell divisions. In recent years, basic scientists have provided more information about the size of the stem cell compartment and the frequency of stem cell mutations in various tissue types. Vogelstein and Tomasetti used the existing literature to plot the total number of stem cell divisions against the lifetime risk of cancer in 31 tissue types, finding an essentially linear correlation.
Adult stem cells are specialized cells that are capable of cell division without differentiation and are required to regenerate and repair tissue. For example, bone marrow stem cells are required to maintain stable levels of red blood cells, white blood cells, and platelets over a lifetime. Scientists have long known that the process of DNA replication, essential for cell division, is prone to errors, and that random genetic changes are more likely to accumulate in tissues where cells divide more frequently. Since cancer is likely a result of errors in DNA replication, it follows that cancer is more likely to occur in tissues that have a lot of stem cells and in tissues with more frequent stem cell divisions; i.e., the probability of a cancer randomly developing in a specific tissue is proportional to the total number of stem cell divisions in that tissue. The work by Vogelstein and Tomasetti strongly supports this hypothesis.
Compared to other cancers, lymphomas are unique because they arise from cells that undergo additional stages of replication beyond the stem cell compartment. Moreover, during these additional periods of lymphocyte replication, DNA mutation is encouraged to occur at a rate unlike that seen in any other cell. We all benefit from the ability of our normal lymphocytes to evolve as they mature—our immune systems will have the capacity to fight infections that have not even been invented yet. However, as a result of changes to DNA in the stem cell compartment, the bone marrow, and the lymph nodes, we are also constantly at risk of accumulating mutations that predispose us to lymphoid malignancies. Unremarkably, these mutations appear to be quite common. For 20 years lymphoma researchers have recognized that a substantial proportion of the population has circulating lymphocytes that have acquired genetic changes during normal periods of maturation in the bone marrow that predispose us to various types of lymphoma . These findings support the concept that the number of cell divisions with associated DNA replication and mutation is proportional to the incidence of neoplasms arising from a given tissue.
Despite the apparent randomness of cancer, it is probably not accurate to assume that all cancers, and especially not all lymphomas, are explained solely by bad luck. For example, the normal immune system appears to play a major role in the emergence of lymphomas. People with inherited or acquired immunodeficiencies are predisposed to some lymphomas while people with overactive, auto-reactive immune systems (e.g., rheumatoid arthritis, Sjogren’s syndrome, ulcerative colitis) are predisposed to others, while still other people may be at increased risk for lymphoma as a result of viral or bacterial infections. Some lymphomas appear to cluster in families or races, suggesting a potentially heritable trait. Some lymphomas appear to cluster geographically, suggesting potential environmental factors. There may be a role for behaviors like exercise or diet. Even height has been associated with increased risk for lymphoma. Ambinder and colleagues from Emory have written an excellent review exploring risk factors for follicular lymphoma.
In their recent report, Vogelstein and Tomasetti found a creative way to use existing data to lend strong support to a widely held hypothesis. It is exciting to think what other answers might already exist in current literature, just waiting for a creative mind to ask the right question.