Biology of Cancer: Follicular Lymphoma as a Model of Cancer Progression
To examine entirely new aspects of cancer progression with major therapeutic implications for both follicular lymphoma and cancer in general.
|Project Leaders||Joseph Connors|
|Project Co-Investigators||Marco Marra , Randy Gascoyne , Doug Horsman, Jacquie Schein, Robert Holt , Steven Jones , Martin Krzywinski , Wan Lam, Carolyn Brown, Cheryl Helgason , Andrew Weng , Allen Delaney|
BC Cancer Agency
Genome Sciences Centre
BC Cancer Research Centre
University of British Columbia
The lymphoid malignancies are the fourth most common cancer seen in Canada. Their incidence has increased by 2.0% annually for more than 50 years. Follicular lymphoma is the most common lymphoma (>25% of new lymphoma cases are follicular; annual incidence >1500; prevalence >20,000) and is linked to a specific genetic abnormality in which a part of chromosome 18 moves to chromosome 14 where it is abnormally overexpressed resulting in overproduction of a protein called BCL2, which causes cells not to die despite aging and accumulated genetic errors. Most follicular lymphomas spend years as indolent but widespread disease but eventually give rise to a more rapidly progressive invasive and lethal cancer, diffuse large B-cell lymphoma (10 y survival < 20%). This transformation offers a unique opportunity to study, at the molecular level, how a slow-growing cancer progresses into a lethal disease.
We intend to use this extensive past experience and these new genomic techniques to examine the biology of follicular lymphoma in more complete detail than has been previously possible. Improved fundamental understanding of the genetics predisposing to development of lymphoma should lead, for the first time, to potential methods of early detection or even prevention. Isolation of the crucial genetically driven steps in lymphoma progression will immediately suggest novel targets for new treatments.
Our research plan is composed of four interactive modules encouraging cross-communication so that each module enhances and guides the other three. The first module will focus on a very recently created model mouse which is genetically programmed for overexpression of BCL2. We will be able to isolate and characterize the multiple effects of this abnormality. The second module will focus on the chromosomal abnormalities that accumulate as lymphoma develops and progresses. We will focus on chromosome 12 (abnormal in 20% of follicular lymphomas); the X-chromosome (the female sex chromosome) (men develop lymphoma more frequently than women); and paired specimens before and after the follicular lymphoma changes from a slow growing cancer to a fast growing lethal type. The third module will directly examine how the cancer cells of follicular lymphoma differ from normal cells at the most basic level, that of the genes themselves. Using a very powerful new technique that allows examination of the entire genetic code of the malignant cells, the whole genome (the entire set of genes that determine how our cells behave) of follicular lymphoma cells will be examined in minute detail allowing us to find many previously unidentified genetic abnormalities present at diagnosis and the new abnormalities that develop as this cancer progresses.
Recent Publications Arising from this Research:
Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. 2010. Nature Genetics [Epub January 17, 2010 ahead of print]. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, Paul JE, Boyle M, Woolcock BW, Kuchenbauer F, Yap D, Humphries RK, Griffith OL, Shah S, Zhu H, Kimbara M, Shashkin P, Charlot JF, Tcherpakov M, Corbett R, Tam A, Varhol R, Smailus D, Moksa M, Zhao Y, Delaney A, Qian H, Birol I, Schein J, Moore R, Holt R, Horsman DE, Connors JM, Jones S, Aparicio S, Hirst M, Gascoyne RD, Marra MA.
For all project related inquires please contact us.
Adrienne Drobnies, Project Manager
Genome Sciences Centre, BC Cancer Agency
Phone: 604-707-5900 x 5436