Project Leaders:   
Douglas Horsman, Wan Lam

Involved Institution:   
BC Cancer Agency

Technology Applications:   
Cancer diagnostics and prognostics

Research Funding Program:   
Applied Health

Cancer research is currently examining genetic changes associated with cancer development and progression. This project will develop and evaluate whole genome array comparative genome hybridization (aCGH), a technique that uses thousands (eg. In one iteration 32,433) small DNA fragments to simultaneously scan the entire genome for copy number changes in tumours. These genetic alterations may be specific for a type of cancer and be used in cancer diagnosis and prognosis. The project will involve collaboration between cancer centres in BC, Alberta and Ontario. Ultimately, aCGH technology will help transform the investigation and management of cancer patients, by enabling the introduction of high-resolution, partially automated and competitively priced technology to assess DNA dosage changes in cancer.

The development of human cancers has been attributed to acquired changes in DNA sequence. Over time, DNA is subject to damage and usually the damage is repaired or the cell is marked for an organized, pre-programmed death. But occasionally some damage survives, allowing cells to proliferate and this can lead to cancer with uncontrolled cell growth and invasion of other tissues.

There has been extensive research into the genetic changes promoting cancer and one category is dosage alterations. Regions of DNA with an abnormal gain or loss may give the location of genes responsible for cancer development or progression. Traditional cytogenetic techniques have led to the identification of characteristic duplications and deletions associated with different types of cancers. To refine these duplication-deletion profiles, comparative genomic hybridization (CGH) with normal control metaphase as the hybridization target has been used but the resolution is still too low (5 to 10 Mb) to isolate specific genes.

This project will develop and validate the whole genome array CGH (aCGH) as a high-resolution tool to identify copy number changes in tumours. Currently, the array is designed based on 32,433 small DNA fragments that span the entire genome. In fact, these DNA fragments were generated from the annotated BAC library used to sequence the human genome. This array has detected single copy dosage changes in cell lines and clinical samples. Plus, the aCGH array has detected novel duplication-deletions in cancers, showing the enormous potential of this technique.

Any identified dosage alterations are verified by other techniques such as locus-specific FISH (fluorescent in situ hybridization). Other technical improvements proposed include the optimization of procedures, development of bioinformatics tools and the reduction of costs.

This project intends to create a duplication-deletion profile for specific subtypes of cancer: lymphoma, lung, brain, and ovary. aCGH will be performed on the DNA of at least 70 tumours per cancer type and the resulting aCGH profiles will be correlated with histology and clinical data for diagnostic, prognostic and predictive associations.

This project will develop and validate aCGH for research and routine clinical applications. Whole genome aCGH will integrate with other techniques under development, helping to change cancer investigation, early detection and treatment.