Characterisation of Candidate Colorectal Cancer Genes Identified by Microarray and SSH Analysis

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Bowel cancer is one of the leading causes of cancer death in Australia today. If diagnosed early, surgery cures most patients. Unfortunately, symptoms often are not present until the cancer is advanced. In these cases surgery is still performed but sometimes all the cancer cannot be removed or it comes back after surgery. We need better ways to identify patients in whom the cancer is likely to return and better chemotherapy drugs to treat cancer not able to be removed surgically. Recently it has been recognised that there are different subgroups of bowel cancer. One of these subgroups contains changes in the DNA called microsatellite instability, MSI-H for short. MSI-H cancers are less likely to come back after surgical removal and there is some evidence that they respond differently to chemotherapy. All cancers develop due to changes in their genetic material which make the cancer cells behave more aggressively than normal cells. We think that MSI-H bowel cancers have different changes in their genetic material compared to non-MSI-H bowel cancers. Understanding what these differences are would allow a better understanding of why bowel cancers do or do not come back after surgery. It would also allow chemotherapy treatments to be individualised according to genetic changes in the cancer. We have already used DNA chip technology to identify a large number of genetic differences between MSI-H and non-MSI-H bowel cancers. In this project we want to examine the most important of these in more detail. We will replicate these changes in cells cultured in the laboratory to see if the changes really do affect the behaviour of cancer cells. We will then look for what kind of genetic damage has led to the change. For key genetic changes, we will then examine our large tumour bank of bowel cancers collected with patients' consent over many years. We will look to see if the genetic changes really do predict the cancers' behaviour and response to treatment.