By Diane Mar-Nicolle
More than 8,000 Canadians were diagnosed with Non-Hodgkin Lymphoma (NHL) last year, making it the sixth most common cancer in Canada. The most prevalent form of NHL is diffuse large B-cell lymphoma (DLBCL). Depending on the sub-type of DLBCL, the five-year survival rate is between 35 and 60 per cent.
Ryan Morin, professor and researcher in SFU’s Department of Molecular Biology and Biochemistry (MBB), and MBB PhD candidate Sarah Arthur, have been studying the genetic mutations that can lead to DLBCL, and have made an interesting discovery.
Morin explains that DLBCL is a genetically complex cancer because there are 100 or more genes that can mutate and contribute to onset of the disease. These mutations have commonly been discovered in the “coding” regions of the genome, which directly affect how proteins are formed. However, roughly 98 per cent of the genome is so-called “non-coding” DNA and much of it has no known function.
“Until recently, the focus in cancer genetics in general, including lymphoma, was to ignore mutations affecting these regions and to instead focus on the two per cent to which we can more easily ascribe function,” says Morin. “In this study, however, we describe a mutation in a non-coding region that does not change the part of our DNA that directs the formation of protein.”
Morin and Arthur became intrigued when they noticed that about one third of study subjects with one sub-type of DLBCL showed some form of mutation affecting the NFKBIZ gene most of these did not change the gene in a way that would be expected to modify its protein product.
Arthur says this finding is critical because it is the first time that a mutation has been discovered in the three prime untranslated region (3’-UTR) of a gene. This structure is important in maintaining the stability of the ribonucleic acid (RNA) copy of genes known as messenger RNA.
She explains that cancers are normally caused by mutations in DNA that directly change the gene product (protein).
“So we don’t know that much about mutations in the 3’-UTR. These sections do not make the protein, which is where cancers start, but some of them help to regulate when and how much of the protein is made.”
In this case, the team found that an abundance of the protein from an oncogene known as NFKBIZ, resulting from UTR mutations described here. This, in turn, is thought to activate what is known as the NF-kappaB pathway, a regulatory system in cells that can drive the growth of cancer cells and is thought to make DLBCL more difficult to treat.
The team is intent on learning more about the function of NFKBIZ and how the mutation is involved in cancer.
Arthur says that if the NFKBIZ gene proves to be an important player in DLBCL, it will be useful in helping clinicians decide which drugs will be most effective in treating patients with DLBCL.
“Having a mutation in this gene may make patients more resistant to some drugs, while susceptible to others,” she says.
“This where personalized medicine could come into play. Treating patients based upon mutations specific to their cancer will correspond to better treatment outcomes and give patients the best chance of being cured.”
The study was published in Nature Communications.
Morin is a Michael Smith Foundation for Health Research Scholar. The study was also supported by the Terry Fox Research Institute.
Simon Fraser University