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

在今天的澳大利亚，肠癌是癌症死亡的主要原因之一。如果及早诊断，手术可以治愈大多数患者。不幸的是，直到癌症发展到晚期，症状才会出现。在这些情况下，仍然会进行手术，但有时无法切除所有的癌症，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，并需要更好的化疗药物来治疗无法通过手术切除的癌症。最近人们认识到，肠癌有不同的亚群。其中一个亚组包含DNA的变化，称为微卫星不稳定，简称MSI-H。MSI-H癌症在手术切除后复发的可能性较小，而且有证据表明，它们对化疗的反应不同。所有癌症的发生都是因为它们的遗传物质发生了变化，这使得癌细胞的行为比正常细胞更具侵略性。我们认为，与非MSI-H肠癌相比，MSI-H肠癌的遗传物质有不同的变化。了解这些差异将有助于更好地理解肠癌手术后复发或不复发的原因。它还将允许根据癌症的基因变化进行个性化的化疗。我们已经使用DNA芯片技术来鉴定MSI-H和非MSI-H肠癌之间的大量基因差异。在这个项目中，我们想要更详细地检查其中最重要的部分。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，我们将寻找是哪种基因损伤导致了这种变化。对于关键的基因变化，我们将检查我们多年来在患者同意下收集的肠癌大型肿瘤库。我们将观察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.