Biology of Cancer: Insights from Genomic Analyses of Lymphoid Neoplasms
We are applying our Illumina sequencing and bioinformatics pipelines to the genome-wide analysis of lymphomas. This will allow the identification of all of the genes being expressed by the lymphoid cells, the presence of mutated genes and chromosome rearrangements, as well as enabling the recognition of proteins which could be targetted by anti-cancer treatments.
| Project Leaders | Marco Marra , Joseph Connors , Randy Gascoyne , Doug Horsman |
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| Project Co-Investigators | Steven Jones , Martin Hirst , Jacquie Schein, Ryan Morin, Allen Delaney |
| Involved Organizations | |
| Funding Agencies |
lymphoid-neoplasm
Overview
The physical characteristics of cancer cells often result from the uncoordinated expression of specific genes and gene products and from the production of mutated (mutation = a genetic change from normal) proteins with new biological properties. In order to study the mis-regulation of gene expression and identify novel gene structures in the greatest detail possible, our project aims to apply Affymetrix arrays, bioinformatics and the latest sequencing technology available from Illumina, to the analysis of transcriptomes, mutations and gene structure in lymphoid tumours as compared to normal cells.
This research project has four specific goals:
- Compare miRNA expression in cancer versus normal cells. MicroRNAs are tiny (~21 to 24 basepairs) single stranded nucleic acids which down regulate (i.e. turn off or turn down) the expression of genes with which they share regions of sequence similarity. These have been shown to be important in several cancers. The expression of known and novel miRNAs will be studied. MicroRNAs and the genes that they regulate, could prove to be important targets for drug treatment or as indicators of disease.
- Sequence the Lymphoma genome. Randomly primed cDNA libraries will be constructed and sequenced using the Illumina system to generate more than two billion base pairs of sequence information for each cancer and control (normal cells) sample. This sequence information will allow us to discover cancer mutations and to study expressed gene structure (i.e. identify gene rearrangements).
- Compare gene expression in Cancer versus normal (control) cells. Affymetrix exon expression arrays will be used to analyze each of the cancer and control samples in order to identify differences in the sets of genes expressed and the relative amount of each gene product, as well as to match target genes with the miRNAs identified previously. This research will give us information explaining the fundamental differences between a lymphoma cell and a healthy cell.
- Drug Discovery. We will use molecular docking approaches to identify candidate small molecule inhibitors of target gene products, chosen due to their expression patterns, mutational status, and structural properties. Finally, we will test these potential candidate inhibitory compounds for their usefulness by examining their effects in cell cultures.
Taken together, the DNA sequence-based information we discover will identify RNA and protein targets and markers, which can be used as points of attack in the treatment of Lymphoma.
Recent Publications by our Research Team:
DNA methylation signatures define molecular subtypes of diffuse large B cell lymphoma.Shaknovich R, Geng H, Johnson NA, Tsikitas L, Cerchietti L, Greally JM, Gascoyne RD, Elemento O, Melnick A. Blood 2010 Jul 7. [Epub ahead of print]
High resolution analysis of follicular lymphoma genomes reveals somatic recurrent sites of copy-neutral loss of heterozygosity and copy number alterations that target single genes.Cheung KJ, Delaney A, Ben-Neriah S, Schein J, Lee T, Shah SP, Cheung D, Johnson NA, Mungall AJ, Telenius A, Lai B, Boyle M, Connors JM, Gascoyne RD, Marra MA, Horsman DE.Genes, Chromosomes and Cancer. 2010 Aug;49(8):669-81.
Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. 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. Nat Genet. 2010 Feb;42(2):181-5.
Hypoxia-inducible factor-1 {alpha} expression predicts superior survival in patients with diffuse large B-cell lymphoma treated with R-CHOP. Evens AM, Sehn LH, Farinha P, Nelson BP, Raji A, Lu Y, Brakman A, Parimi V, Winter JN, Schumacker PT, Gascoyne RD, Gordon LI.J Clin Oncol . 2010 Feb 20;28(6):1017-24.
Long-term outcomes for patients with limited stage follicular lymphoma: involved regional radiotherapy versus involved node radiotherapy.Campbell BA, Voss N, Woods R, Gascoyne RD, Morris J, Pickles T, Connors JM, Savage KJ.Cancer. 2010 Aug 15;116(16):3797-806.
Contact Information
For all project related inquires please contact us.
Armelle Troussard, Projects Manager
Genome Sciences Centre, BC Cancer Agency
Email: armellet@bcgsc.ca
Phone: 604-675-8000 x 7968
Fax: 604-675-8178