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

大多数乳腺癌家族的致病基因仍不清楚。BRCA1和BRCA2基因可以防止癌症的发展，代表了一类统称为“肿瘤抑制因子”的基因。这些基因的特点之一是，在携带一个遗传突变副本的个体出现的肿瘤中，它们显示出基因正常副本的丢失。这项建议的主要目的是利用这一现象来识别易患家族性乳腺癌的新的肿瘤抑制基因。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丢失了一个基因副本，并在特定的染色体区域保留了相同的副本时，候选抑癌基因就会被识别出来。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。将识别出所有肿瘤都丢失了完全相同的染色体部分的家族。接下来，我们将利用人类基因组的整个序列已经完成这一事实来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这些“候选基因”中的哪些实际上对该家族中的癌症负有责任。随后，我们将调查其他有乳腺癌病史的家庭，看看有多少可以通过这种基因的突变来解释。使用这一强大的方法，我们有可能识别出比乳腺癌基因更多的东西。识别新的乳腺癌易感基因将对直接受影响的家族具有重大的临床意义，如果后来发现相同的基因(或途径)与其他家族性或散发性乳腺癌的病因有关，则具有更广泛的相关性。

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.