Use of comparative genomics to identify novel regulators of melanoma progression

描述(申请人提供)：我们的研究试图定义驱动黑色素瘤进展的基因变化，黑色素瘤是最具侵袭性和最致命的皮肤癌。新技术已经产生了大量描述癌症基因组的数据。这些研究是回溯性的。他们提供了单个癌症中存在的缺陷的目录，但没有区分促进肿瘤的基因组变化和那些在肿瘤进展过程中偶然出现的变化。要区分这一区别，必须进行功能研究，而在许多癌症中，候选基因组变化的清单可能相当大。为了分析基因拷贝数变异的变化，我们使用了跨物种比较和保守的斑马鱼黑色素瘤模型的功能研究。由于黑色素瘤进展中涉及的一些基因组变化在其他癌症中也可以看到，我们的研究可能会为癌症的发展提供更广泛的见解。我们定义的基因变化可能有助于疾病的诊断和预后指标，以及黑色素瘤和潜在的其他类型癌症的治疗目标。本项目的两个研究领域是：1.确定人类和斑马鱼黑色素瘤共有的基因拷贝数变化，并使用功能筛选来鉴定新的黑色素瘤基因。黑色素瘤的形成机制在斑马鱼和人类之间是保守的。通过确定斑马鱼和人类黑色素瘤常见的基因组变化，我们可以发现与黑色素瘤发生有关的新基因和新机制。2.研究BMP家族配体GDF6在黑色素瘤进展和黑素细胞发育中的作用。上述比较研究已经确定了一个很好的黑色素瘤候选基因GDF6。该BMP家族配体在人类和斑马鱼黑色素瘤中反复扩增和过度表达，其在胚胎发生过程中的表达模式表明它在黑素细胞发育过程中起着调节作用。我们将评估GDF6和BMP信号如何参与黑色素瘤的形成，可能是通过调节黑素细胞的分化和增殖。

DESCRIPTION (provided by applicant): Our studies seek to define genetic changes that drive progression of melanoma, the most aggressive and deadliest skin cancer. New technologies have yielded a wealth of data describing the genomes of cancers. These studies are retrospective. They offer a catalog of defects present in individual cancers but do not discriminate between tumor-promoting genomic changes and those changes that arose incidentally during tumor progression. Functional studies are necessary to draw this distinction, and in many cancers the list of candidate genomic changes can be quite large. To parse through changes in gene copy number variation we use cross-species comparisons and functional studies with a conserved zebrafish melanoma model. Since some of the genomic changes involved in melanoma progression are seen in other cancers, our studies may provide broader insights into cancer development. The genetic changes we define may be useful as diagnostic and prognostic indicators of disease as well as therapeutic targets for melanoma and potentially other types of cancer. The two areas of study in this project are: 1. Define gene copy number changes that are shared between human and zebrafish melanomas, and use functional screening to identify new melanoma genes. Mechanisms of melanoma formation are conserved between zebrafish and humans. By determining genomic alterations common to zebrafish and human melanomas we can uncover new genes and mechanisms involved in melanomagenesis. 2. Examine the BMP-family ligand GDF6 for its roles in melanoma progression and melanocyte development. The comparative studies above have already identified an excellent candidate melanoma gene, GDF6. This BMP-family ligand is recurrently amplified and overexpressed in human and zebrafish melanomas, and its expression pattern during embryogenesis suggests a role in regulation of melanocyte development. We will assess how GDF6, and BMP signaling in general, participate in melanoma formation, perhaps by regulating the differentiation and proliferation of melanocytes.