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Genetic Studies of Non-Hodgkin Lymphoma
With the completion of the sequencing of the human genome, much attention has been centered on the
study of human genetic variability in disease risk. Single nucleotide polymorphisms (SNPs) are the most
common source of human genetic variation, and they are, undoubtedly, a valuable resource for
investigating the genetic basis of cancers such as lymphoma. Although the majority of these gene variants
do not influence disease risk, certain SNPs may influence susceptibility to disease, disease severity,
disease progression or other outcomes related to the disease. One of the biggest current challenges in
biomedical research is the identification of these gene variants. In genetic epidemiology, a genome-wide
association study (GWAS) is an examination of hundreds of thousands of variations, generally SNPs, in a
sample population. These studies normally compare the variations of two groups of participants: people
with the disease (cases) and similar people without the disease (controls). If the frequency of particular
SNPs vary between the cases and controls, the variations are said to be "associated" with the disease.
In our group, we are investigating how human genetic variation influences the risk of lymphoma. Using
GWAS studies, we searched for variations in the genome associated with major types of non-Hodgkin
lymphoma (NHL) in a group of over 1400 NHL cases and controls from the San Francisco Bay Area. We
found several SNPs that were statistically significantly more frequent in follicular lymphoma cases than
in the controls, and therefore are potentially involved in risk of the disease. These SNPs were mainly
located in the human leukocyte antigen (HLA) region, a part of the genome that contains a large number
of genes related to immune system function, and that plays an important role in several other diseases,
particularly in autoimmune disorders. Further analyses of the HLA region identified additional genetic
differences between the follicular lymphoma cases and controls suggesting that HLA gene variants may
play an important role in disease susceptibility. Some of these HLA gene regions have also been shown
to influence risk of rheumatoid arthritis and type 1 diabetes.
Although these findings have been validated by other studies within the large lymphoma consortium,
InterLymph, much caution must be taken when extrapolating the results. As with any other cancer, NHL
is a very complex disease that arises from the interaction between multiple variations in different genes
and non-genetic factors, such as environmental exposures and lifestyle. Further studies will be needed to
determine how these gene-environment interactions influence disease risk.