Project Leaders:   
Marco Marra, Joseph Connors, Randy Gascoyne

Involved Institutions:   
BC Cancer Agency, University of British Columbia

Technology Applications:   
New diagnostic and prognostic markers; Drug development

Research Funding Program:   
Competition III

GE³LS Activity:   
Health Technology Assessment

Follicular lymphoma (FL), the most common type of lymphoma, is a cancer of the cells of the immune system. Follicular lymphoma is associated with a specific genome rearrangement where parts of chromosomes 14 and 18 have exchanged. This rearrangement is an initiating event for FL but insufficient without additional mutation events for cancer development. Furthermore, there may be more genome rearrangements to progress from FL to a more aggressive form of the disease, diffuse large B-cell lymphoma. To understand the relationship between rearrangements and disease, this project will identify rearrangements in the FL genome and then analyze the rearrangements to determine their effect on gene structure. Because this is the first in depth genome profiling of human cancers, recurrent genomic rearrangements will advance knowledge not only about lymphoma but about cancer in general. Understanding the dysfunctions in lymphoma will permit researchers to develop new diagnostic and prognostic markers and possibly new therapies.

Genomic rearrangements can cause disease, including cancers. Certain cancers are associated with stereotypical rearrangements, such as follicular lymphoma (FL) – 80 to 90% of North American and European FL is associated with the reciprocal translocation t(14;18)(q32;q21). Although most FL is associated with t(14;18), animal models suggests that the rearrangement alone is insufficient for cancer. Plus, the translocation is found in healthy individuals, supporting the idea that further genomic rearrangements are required before progression to FL. The progression from FL to a more aggressive disease, diffuse large B-cell lymphoma, may also involve genome rearrangements that disturb genes normally blocking this progression. Therefore, this group will investigate the relationship between genomic rearrangements and FL, using the tools developed for the Human Genome Project.

Twenty-four bacterial artificial chromosome (BAC) clone libraries will be constructed from 24 lymphoma tissue samples, with each library representing a 6-fold redundant coverage of a different lymphoma genome. Using a version of the technology used to map the human and mouse genomes, these BACs will then be fingerprinted with approximately 5-fold coverage. This analysis will then be compared to ‘standard’ fingerprints from the human genome reference sequence to identify BACs with an excess or shortage of chromosomes, suggesting a rearrangement. Lymphoma BACs with rearrangements will then be sequenced to confirm and investigate the nature of the rearrangement.

This strategy is a precedent-setting survey of lymphoma genomes and the sequence analysis of those rearrangements most likely to contribute to disease development and progression. The knowledge will help the cancer field develop new screening and diagnostic tools and potentially develop new treatments.