Grant: CIHR Fellowship

Non-Hodgkin lymphoma (NHL) is a specific type of cancer in which an abnormal growth of cells of the immune system produces a tumour. The cells in these tumours often have a type of chromosome damage called a translocation, where two chromosomes are incorrectly joined together. These translocations may occur when genes that are responsible for repairing damaged DNA are not functioning properly. Although most of the DNA sequence is similar between individuals, there are a number of DNA sequence differences, known as genetic variants. Previous studies in my lab looked at genetic variation in six DNA repair genes in patients with NHL and control (unaffected) individuals. They found that a common DNA sequence variant at one of these genes, called H2AX, was much more frequent among the patients than the controls. Individuals who carry this gene variant have twice the risk of NHL as those who do not have it. Since this DNA sequence feature is very common in the population, it is predicted that 23% of NHL could be caused by this gene variant. The goal of this project is to determine why individuals with the H2AX gene variant have increased risk of NHL. The DNA sequence variant is found at the part of the gene that controls how H2AX is regulated and may affect how this gene is turned on and off. Since H2AX is a gene involved in repairing damaged DNA, if it is not regulated correctly, damaged DNA may not be properly repaired, leading to the translocations found in NHL tumours. Using molecular techniques and cell culture assays, I will look at how this DNA sequence variant affects regulation of the gene and influences the ability of the cell to repair and survive DNA damage. Understanding how and why this specific gene variant increases risk for NHL will lead to a better knowledge of how this cancer develops. This information will eventually be useful for identifying new drug targets and therapies for NHL, and may provide insight into the development of other cancers as well.