Genome-wide study of loss of heterozygosity using high density SNP arrays to identify breast cancer predisposition genes

使用高密度 SNP 阵列识别乳腺癌易感基因的杂合性丢失全基因组研究

• 批准号: nhmrc : 400108
• 负责人: Prof Ian Campbell
• 金额: $ 36.18万
• 依托单位: The University of Melbourne
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2006
• 资助国家: 澳大利亚
• 起止时间: 2006-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/genome-wide-study-predisposition-genes/98092
• 关键词: Genome; wide; study; loss; heterozygosity

The genes responsible for the majority of breast cancer families remain unknown. The genes BRCA1 and BRCA2 can prevent the development of cancer and represent a class of gene known collectively as 'tumor suppressors'. One of the hallmarks of these genes is that they show loss of the normal copy of the gene in tumors that arise in individual carrying one inherited, mutated copy. The broad aim of this proposal is to exploit this phenomenon to identify novel tumor suppressor genes that predispose to familial breast cancer. This will be done by analyzing tumors from families that do not have either BRCA1 or BRCA2 mutations. Candidate tumor suppressor genes will be identified when tumors from different individuals in the same family all appear to have lost one copy of a gene, and retained the same copy, in a particular chromosomal region. We study tumours from non-BRCA1-2 breast cancer families using genetic techniques that are able to rapidly and accurately identify which parts of the chromosomes have been lost. Families will be identified in which all the tumors have lost exactly the same part of the chromosome. Next, we will exploit the fact that the entire sequence of the human genome is completed to find out which genes are located within the candidate region. We will then apply other technologies to identify which of these 'candidate genes' is actually responsible for the cancer in that family. Following this, we will investigate other families with a history of breast cancer to see how many can be accounted for by mutations in this gene. It is possible that we may identify more than on breast cancer gene using this powerful approach. Identification of new breast cancer predisposition genes would have major clinical relevance to the families directly affected, and much wider relevance if the same gene (or pathway) is later found to be involved in the causes of other familial or sporadic breast cancers.

导致大多数乳腺癌家族的基因仍然未知。BRCA1和BRCA2基因可以预防癌症的发展，代表了一类被统称为“肿瘤抑制因子”的基因。这些基因的一个特点是，当个体携带一个遗传的、突变的拷贝时，它们会显示出肿瘤中正常基因拷贝的丢失。这一建议的主要目的是利用这一现象来鉴定易患家族性乳腺癌的新型肿瘤抑制基因。这将通过分析来自没有BRCA1或BRCA2突变的家族的肿瘤来完成。当来自同一家族中不同个体的肿瘤似乎都失去了一个基因的一个拷贝，并在特定的染色体区域保留了相同的拷贝时，候选肿瘤抑制基因将被识别出来。我们使用基因技术研究非brca1 -2乳腺癌家族的肿瘤，这种技术能够快速准确地识别染色体的哪些部分已经丢失。这些家族中所有的肿瘤都失去了染色体的同一部分。接下来，我们将利用整个人类基因组序列已经完成的事实，找出哪些基因位于候选区域内。然后，我们将应用其他技术来确定哪些“候选基因”实际上是导致该家庭癌症的原因。在此之后，我们将调查其他有乳腺癌病史的家庭，看看有多少是由该基因突变引起的。使用这种强大的方法，我们有可能识别出不止一种乳腺癌基因。新的乳腺癌易感基因的鉴定将对直接受影响的家族具有重要的临床意义，如果相同的基因（或途径）后来被发现与其他家族性或散发性乳腺癌的病因有关，则具有更广泛的意义。