Using array CGH to identify prostate cancer genes

描述(申请人提供)：前列腺癌是大多数西方国家最常见的非皮肤癌。双胞胎和家族性研究表明，家族史是前列腺癌的明确危险因素。然而，尽管进行了大量的努力和多重连锁研究，但只发现了几个导致前列腺癌易感性的基因变化，这只解释了一小部分家庭。鉴于遗传性前列腺癌的复杂性，需要新的方法来补充传统的连锁分析方法，以辅助前列腺癌的基因识别。我们建议与国际前列腺癌遗传学联合会成员合作，在遗传性前列腺癌家族中使用基于阵列的比较基因组杂交(ACGH)来进一步识别遗传性前列腺癌的重要基因。在特定的目标1中，我们将使用aCGH来描述遗传性前列腺癌家族中的前列腺癌的染色体扩增和缺失的特征，并将这些发现与先前发现的连锁区域相关联。在特定的目标2中，我们将确定家庭成员之间是否存在共同的染色体丢失或获得区域，这表明共同的基因改变的位置。作为一个探索性的目标，我们将对aCGH数据进行聚类分析，以探索我们是否可以利用肿瘤特征来区分家系，从而降低前列腺癌连锁研究中的遗传异质性。总而言之，这些目标代表着在识别前列腺癌易感基因方面向前迈出的重要一步。此外，它们还将提供有关前列腺癌发展中体细胞染色体扩增和缺失的重要信息，其规模是以前无法实现的。识别遗传性前列腺癌的基因将为高危病例和普通人群中与前列腺癌发展相关的遗传变异和生物学提供重要的见解，进一步提高我们预测谁是前列腺癌高危人群的能力。

DESCRIPTION (provided by applicant): Prostate cancer is the most commonly diagnosed non-skin cancer in most western countries. Family history is well established as a clear risk factor for prostate cancer, as demonstrated by twin and familial studies. However, despite major efforts and multiple linkage studies, only a few genetic changes have been identified that confer susceptibility to prostate cancer, which explain only a minority of the families. Given the complexity of hereditary prostate cancer, novel approaches complementary to the traditional approach of linkage analysis, are needed to assist with gene identification in prostate cancer. We propose to use array based comparative genomic hybridization (aCGH) in prostate cancers from hereditary families to further the identification of genes important in hereditary prostate cancer, in collaboration with members of the International Consortium for Prostate Cancer Genetics. In Specific Aim 1, we will characterize the chromosomal amplifications and deletions in prostate cancers from hereditary prostate families using Acgh and correlate the findings with previously identified regions of linkage. In Specific Aim 2, we will determine if there are common regions of chromosomal loss or gain shared between family members suggesting the locus of a shared genetic change. As an exploratory aim, we will perform cluster analyses on the aCGH data to explore whether we can differentiate between families using tumor profiles, and thus decrease the genetic heterogeneity in prostate cancer linkage studies. Together these aims represent a significant step forward in the effort to identify prostate cancer susceptibility genes. In addition, they will provide important information about somatic chromosomal amplifications and deletions in prostate cancer development on a scale not previously achievable. Identifying genes in hereditary prostate cancer will provide important insights into genetic variation and biology associated with prostate cancer development both in high-risk cases and the general population, furthering our ability to predict who is at highest risk of prostate cancer.