Biology of Lymphoma Development
The development of all cancers, including lymphomas, involves the alteration (mutation) of DNA, which is the genetic material within each cell controlling all biological functions of that cell. With increasing numbers of genetic alterations, a cell gains or loses important biological functionality. Eventually, the genetically altered cell and its clones behave increasingly abnormally resulting in malignant biologic behavior–cancer. Most important among these alterations are changes to certain genes that normally inhibit continued unchecked growth of a cell. Loss of these important inhibiting functions allows cells to continually divide and replicate into a mass-forming clone of nearly identical abnormal cells. Other important genetic alterations include changes to the production of cell adhesion molecules, allowing cells to migrate in abnormal ways and to grow (and even thrive) in otherwise hostile cellular milieus away from their normal locations. Other mutations allow abnormal clones to evade a host’s normal immune response, which typically detects and kills abnormal cells.
Although some genetic syndromes predispose to certain malignancies, the overwhelming cause of most lymphomas is the acquisition of genetic changes during an individual's life, a result of exposures that increase the risk of these genetic changes as noted above. The causes of these genetic changes represent the risk factors that are the ultimate cause of the malignancy. Some environmental toxins have multiple effects that are both genotoxic and promotional. This means that in addition to producing mutations, they also directly enhance increased cell replication and survival, further enhancing the malignant process and potentially leading to such transformation events. The continued exposure to such agents, over years, will increase the risk and evolution of these sequential changes, ultimately leading to tumor progression to overt malignant lymphoma/leukemia.
Like virtually all cancers, lymphomas and leukemias originate from DNA changes. Some lymphomas are linked to family history, that is, inherited germline mutations in susceptibility genes with which the patient is born. However, the overwhelming cause of most lymphomas is acquisition of genetic changes during an individual's life, often as a result of exposures that increase the risk of these genetic changes. The distinct lymphoma subtypes are often characterized by specific gene or chromosomal changes, such as seen in follicular lymphoma, in which there is translocation (crossing of genetic material from one chromosome to another) of DNA between chromosomes 14 and 18, resulting in activation of the BCL-2 oncogene. Again, the causes of these genetic changes represent the risk factors that are the ultimate cause of the malignancy.