GENOMICS OF HUMAN NEUROBLASTOMA

描述（由申请人提供）：神经母细胞瘤是儿童早期最常见的实体瘤，也是婴儿期诊断的所有类型中最常见的癌症。尽管对高危患者（占所有病例的50%）采取了积极的治疗方法，但这些儿童中的大多数仍然死于疾病。神经母细胞瘤的临床特征是异质性，肿瘤进展的可能性差异很大。导致神经母细胞瘤发展的分子途径是复杂的，可以解释观察到的临床异质性。侵袭性和转移性神经母细胞瘤表现出一致的重排，可细分为两个主要亚群：在最具侵袭性的亚群中（40%的高危病例），1p缺失和MYCN癌基因的高水平扩增，而在另一个亚群中，11q物质和MYCN单拷贝的3p LOH不平衡丢失。我们假设，在没有癌基因扩增的情况下，至少两个位于3p和11q的肿瘤抑制基因的协同失活是形成高风险神经母细胞瘤表型所必需的。本研究旨在实现以下目标：1)利用高分辨率阵列比较基因组杂交（aCGH）技术，在一组具有代表性的原发性神经母细胞瘤肿瘤中鉴定和定位3p和11q缺失；2)确定3p和11q缺失对区域特异性基因表达、临床表型和患者预后的影响；3)结合结构和功能方法鉴定一个3p神经母细胞瘤抑制基因。将一组有代表性的人类神经母细胞瘤肿瘤的aCGH和表达谱数据进行关联，将使我们能够优先考虑最有希望的神经母细胞瘤抑制基因，这些基因的改变是高风险表型所必需的，并最终利用它们作为这种通常致命的儿童癌症的治疗靶点。

DESCRIPTION (provided by applicant): Neuroblastoma is the most common solid tumor of early childhood and the most common cancer of any type diagnosed during infancy. Despite an aggressive approach for the treatment of high-risk patients (50% of all cases), most of these children still die of their disease. The clinical hallmark of neuroblastoma is heterogeneity, with the likelihood of tumor progression varying widely. The molecular pathways leading to the development of neuroblastoma are complex and may explain the observed clinical heterogeneity. Invasive and metastatic neuroblastomas show consistent rearrangements and can be subdivided into two major subsets: 1p deletion and high-level amplification of the MYCN oncogene in the most aggressive subset (40% of high-risk cases), and unbalanced loss of 11q material and 3p LOH with MYCN single-copy in the other. We hypothesize that in the absence of oncogene amplification, coordinate inactivation of at least two tumor suppressor genes located at 3p and 11q is required to develop a high-risk neuroblastoma phenotype. This proposal seeks to achieve the following aims: 1) Identify and map 3p and 11q deletions in a representative set of primary neuroblastoma tumors using high-resolution array-based comparative genomic hybridization (aCGH); 2) determine the influence 3p and 11q deletions have on region-specific gene expression, clinical phenotype and patient outcome; and 3) combine structural and functional approaches for the identification of a 3p neuroblastoma suppressor gene(s). Correlating aCGH and expression profiling data on a carefully annotated set of representative human neuroblastoma tumors will allow us to prioritize the most promising putative neuroblastoma suppressor genes whose alteration is required for a high-risk phenotype, and ultimately exploiting them as therapeutic targets for this often lethal childhood cancer. This proposal describes a 5 year training program that is ambitious, yet feasible. It is designed to allow the candidate to develop the skills and experience required of an independent physician-scientist. The principal investigator will be mentored by leaders in the field of pediatric neuroblastoma research and cancer genomics at both the Children's Hospital of Philadelphia and the University of Pennsylvania. Such an environment will maximize the potential for the principal investigator to establish a scientific niche from which an academic career can be constructed. Successful completion of this project will have an immediate impact on pediatric oncology, but the methodology and data acquired will also likely be relevant to cancer biology in general.