January 27, 2010, Vancouver, BC - Drs. Joseph Connors, Randy Gascoyne and Marco Marra and their team of fellow scientists have discovered a never-before-seen DNA spelling mistake, or mutation, the EZH2 gene of diffuse large B-cell lymphoma and follicular lymphoma, the two most common types of non-Hodgkin lymphoma. The researchers were working in collaboration with the BC Cancer Agency and on research grants funded in part by the Terry Fox Foundation (TFF).

This groundbreaking discovery, published online on January 17 in the prestigious international science journal Nature Genetics, is of particular importance because, in contrast to cancer-related mutations that are often observed in different sites in genes associated with individual tumours, this study identified a mutation found in exactly the same location in samples from different lymphoma patients. Based on previous research, the mutated site is known to be one of the most important amino acids in the proper functioning of EZH2.

"While we know EZH2 is involved in certain types of breast and prostate cancer, it has never before been found mutated in any cancer and was not previously implicated in having a role in lymphomas," said Dr. Connors, chair of the Lymphoma Tumour Group, clinical director of the Centre for Lymphoid Cancer at the BC Cancer Agency, and clinical professor of medical oncology at the University of British Columbia. "The presence of this mutation can be considered a marker that will aid in diagnosing these lymphomas and identifying new therapies for their treatment."

In addition to decoding thousands of genes in malignant cells from 31 patients with diffuse large B-cell lymphoma, the entire genome of a patient with follicular lymphoma was decoded. When researchers found the EZH2 mutation in exactly the same position in many of the cases, they examined the malignant cells of additional patients and found it to be mutated the same way and in the same position in almost one-quarter of the cases with a specific lymphoma subtype. For scientists, this consistent characteristic may potentially be a key discovery in the effort to find a cure for the disease. It is hoped that treatments can be developed to target cancer cells with this particular characteristic, including drugs that would specifically affect cancer cells without side effects to healthy cells.

It is estimated that 1,000 British Columbians will be diagnosed with non-Hodgkin lymphoma this year, and at least 340 of those patients will die from it. The most common type, diffuse large B-cell lymphoma, is an aggressive cancer that can only be cured in about two-thirds of patients. The next most common type, follicular lymphoma, is a slower-growing cancer for which there is currently no cure, but it can be kept in check for long periods of time with relatively mild chemotherapy. EZH2 was found mutated in both types.

This study was one of many cancer-related projects funded in part by the Terry Fox Foundation's New Frontiers initiative. Dr. Joseph Connors, leading the study under a TFF Program Project Grant (PPG) awarded in 2006, has used the funding to further study potential treatment methods into Hodgkin lymphoma, chronic leukemias, and other types of blood-related cancers. The 2006 PPG was used specifically to support molecular biological studies into B-cell lymphomas, which included genetic profiling, genomic analysis, cytogenetic analysis and array comparative genomic hybridization.

"A few years ago scientists studying lymphoma and other cancers understood that specific abnormalities in which parts of one chromosome are broken off and attached to another chromosome played a crucial role in defining lymphoma behaviour. However, the list of such abnormalities was small and fell far short of explaining lymphoma behaviour or response to treatment. Our project has documented, for the first time in a human cancer, that there are hundreds of individual chromosomal, and therefore genetic, changes in lymphoma cells and many of them have not been previously explored," said Dr. Connors. "It is highly likely that similar discoveries can be made in other cancers using the same techniques that have been developed by those members of our research team based at the BC Cancer Agency Genome Sciences Center."

Such discoveries into the fundamental nature of lymphoma cells provide scientists with the understanding needed to develop new methods of treatment. The findings of this study will not only be translated into better future approaches to B-cell and follicular lymphoma, but also pave the way for similar research to be conducted on other forms of cancer. Data obtained from this research can guide the development of new drugs and methods that will specifically target cells with the cancer-linked abnormalities. On potential timelines for potential clinical applications or trials stemming from this study, Dr. Connors was optimistic, noting that screening and selection processes for drugs affecting the EZH2 mutation have already begun.