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

肠癌是当今澳大利亚癌症死亡的主要原因之一。如果早期诊断，手术治愈了大多数患者。不幸的是，症状往往不存在，直到癌症晚期。在这些情况下，仍然进行手术，但有时所有的癌症都不能切除，或者手术后复发。我们需要更好的方法来识别癌症可能复发的患者，以及更好的化疗药物来治疗无法手术切除的癌症。最近，人们认识到肠癌有不同的亚组。其中一个亚群包含DNA的变化，称为微卫星不稳定性，简称MSI-H。MSI-H癌症在手术切除后不太可能复发，并且有证据表明它们对化疗的反应不同。所有癌症的发展都是由于其遗传物质的变化，使癌细胞比正常细胞更具侵略性。我们认为MSI-H肠癌与非MSI-H肠癌相比，其遗传物质发生了不同的变化。了解这些差异将有助于更好地理解为什么肠癌在手术后会或不会复发。它还允许根据癌症的遗传变化进行个性化的化疗治疗。我们已经使用DNA芯片技术来识别MSI-H和非MSI-H肠癌之间的大量遗传差异。在这个项目中，我们想更详细地研究其中最重要的。我们将在实验室培养的细胞中复制这些变化，看看这些变化是否真的影响癌细胞的行为。然后我们将研究是什么样的遗传损伤导致了这种变化。对于关键的遗传变化，我们将检查我们多年来在患者同意下收集的大型肠癌肿瘤库。我们将看看基因变化是否真的能预测癌症的行为和对治疗的反应。

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.