BC Cancer Agency scientists have discovered that a single gene, CIITA, is implicated in almost 40 per cent of primary mediastinal B-cell lymphomas (a type of non-Hodgkin lymphoma) and 15 per cent of all Hodgkin lymphoma cases.
The groundbreaking discovery, published today in the international science and medical journal Nature, identifies for the first time a commonly-occurring gene fusion as a cause in primary mediastinal B-cell lymphoma, and as one of only a handful of times a specific gene has been implicated in the development of Hodgkin lymphoma.
"British Columbia is recognized as a world-leader in cancer research and care," says Vancouver Fairview MLA Margaret MacDiarmid, on behalf of Health Services Minister Colin Hansen. "Discoveries have improved outcomes for cancer patients in British Columbia, Canada and around the world."
The process begins when the CIITA gene breaks off and fuses with another gene (a process called chromosomal translocation). The gene fusion creates a double-whammy for the immune system by a) knocking out a molecule that helps T-cells detect cancerous cells in the body - thereby allowing the cancerous cells to multiply unchecked - and b) increasing the expression of a second molecule that leads to the destruction of T-cells, which are important for attacking cancer cells.
The discovery of this two-fold mechanism—one which disguises cancer cells from detection, so they can proliferate, and the other which eliminates cancer fighting T-cells—creates a one-two punch for the immune system, leaving the body vulnerable to disease.
"The role of the immune system is to fight off disease, including cancer, and for the most part it is highly effective in doing its job," says Dr. Christian Steidl, lead author and scientist at the BC Cancer Agency, an agency of the Provincial Health Services Authority. "But it's always been puzzling how cancer cells are able to evade the immune system and continue to grow. This study gives us unique insight into how they evade immune surveillance by rearranging their chromosomes."
Senior author and principal investigator Dr. Randy Gascoyne, Research Director of the BC Cancer Agency's Centre for Lymphoid Cancer, hopes the discovery will reinvigorate research into cancer immunology. "We've long suspected that a defect in the immune system is somehow implicated in the development of cancer, particularly lymphoid cancers, but research so far has yielded few clues. This is the first time we've been able to identify a concrete genetic mechanism for how that happens in these lymphomas."
After isolating the mutation, researchers validated their findings by examining stored tissue samples from 263 lymphoma patients and their treatment outcomes. Researchers found that the group of primary mediastinal B-cell lymphoma patients with the gene fusion had a poorer outcome. Ten-year survival for this group was 63.6 per cent versus 85 per cent for the group without the gene fusion.
Dr. Joseph Connors, Clinical Director of the BC Cancer Agency's Centre for Lymphoid Cancer and a co-author of this study, notes that, "This discovery has far-reaching implications because we have the potential to develop new biomarkers to more accurately classify primary mediastinal B-cell lymphoma, and those biomarkers could be used for new drug development, as well as to identify patients who may not respond as well to treatment."
The discovery was made in collaboration with the BC Cancer Agency's Genome Sciences Centre, whose next-generation DNA sequencing technology can decode billions of nucleotides at unprecedented speed and whose cutting-edge computer techniques allow rapid interpretation of data.
"In a technical tour de force, the authors have found the first recurring translocations in primary mediastinal B-cell lymphoma," says Dr. Nancy Lee Harris, Professor of Pathology, Massachusetts General Hospital and Harvard Medical School. "These translocations had not been found through routine methods, as they often appear to result from small insertions in the chromosome. The work of Dr. Gascoyne and his team is truly novel."
Lymphoma is the fifth most common cancer in North America and has the fastest growing incidence. Primary mediastinal B-cell lymphoma and Hodgkin lymphoma are two of the most common cancers affecting young people. Each year, about 930 Canadians (about 110 British Columbians) are diagnosed with Hodgkin lymphoma. Approximately 80 Canadians (10 British Columbians) are diagnosed with primary mediastinal B-cell lymphoma. Most are under the age of 40.
"An important part of the Provincial Health Services Authority mandate is to improve the health of British Columbians by advancing research," says Wynne Powell, Board Chair, Provincial Health Services Authority. "It is only through the generation of new knowledge—such as this groundbreaking work by BC Cancer Agency scientists—that we can hope to deliver better and more effective and targeted treatments for cancer patients."
The study was funded in part by grants from the Cancer Research Society (Steven E. Drabin Fellowship), the Michael Smith Foundation for Health Research, the Lymphoma Research Foundation, and through operational funds from the Canadian Institutes of Health Research. Drs. Gascoyne and Connors also receive generous support from the Terry Fox Foundation in the form of a New Frontiers Program Project Grant.
The BC Cancer Agency's Centre for Lymphoid Cancer, led by world-renowned lymphoma experts Dr. Joseph Connors and Dr. Randy Gascoyne, is one of the most prolific research groups in North America. Two major discoveries in 2010 drew international attention and were published in Nature Genetics and the New England Journal of Medicine.
Their team recently launched a major new research initiative, the ANGELYC Project, which will analyze the entire DNA of all lymphoid cancers, to discover and develop new, targeted and more effective treatments for patients and to reduce lymphoid cancer mortality. The BC Cancer Foundation has raised $2.6 million to support this momentous project and to catalyze its potential to leverage external grant funding.
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