Application of genomic approaches to classify retinoblastoma tumors

描述（申请人提供）：视网膜母细胞瘤（Retinoblastoma， RB）是一种儿童眼部肿瘤，如果不及早诊断，可导致失明和死亡。目前，RB患者的治疗取决于诊断时的肿瘤分期。对于那些单侧肿瘤大且无家族史的患者（占所有RB患者的60-70%），去核是治疗的选择。在这些患者的一个子集中，去核后进行辅助化疗以降低肿瘤复发和转移的风险。对于双侧RB病例，切除受影响最严重的一只眼，然后对另一只眼进行全身化疗。尽管有这些治疗方法，30%的双侧和15%的单侧（15%）病例在诊断和去核后的前1至3年内出现新肿瘤复发。这个项目的目标是确定与肿瘤复发风险相关的分子标记。我们假设，通过基于全基因组SNP（单核苷酸多态性）的染色体拷贝数分析，并将这些信息与基于微阵列的基因表达研究相关联，对RB肿瘤的基因组不稳定性进行全面研究，将有助于识别肿瘤生物学和复发风险的分子标记。为了严格验证这一假设，我们提出了一组互补的特定目标，这将利用基因组技术分析RB肿瘤样本和相关的临床数据。目的1：获取RB肿瘤全基因组中染色体区域的损失和增加概况，用于预测该疾病的复发。特异性目的2获取RB肿瘤的基因表达谱，以识别预测疾病复发风险的分子标记。目的3结合目的1和目的2的数据建立RB复发的分子分类器。该项目的结果将是一组标记良好的RB肿瘤的高分辨率全基因组图谱。分析这些数据可以更好地理解RB肿瘤发生的生物学基础。在许多其他类型的癌症中，这些谱已被用于识别可以预测肿瘤复发风险的特定类别的分子特征。分子特征的识别将转化为改善未来儿童RB患者的管理，拯救视力并改变受影响儿童及其家庭的生活质量。视网膜母细胞瘤（RB）是一种儿童眼部肿瘤，如果不及早诊断，可导致失明和死亡。该项目的目的是在更好地了解RB肿瘤发生、进展和复发风险的分子病因的基础上，促进RB患者的管理。为此，我们将利用新的强大的高分辨率基因组图谱技术来测量不同类型RB肿瘤的染色体畸变和基因表达水平。这将使我们能够识别与RB复发风险相关的分子特征。

DESCRIPTION (provided by applicant): Retinoblastoma (RB) is a childhood ocular tumor that can lead to blindness and death if not diagnosed early. Currently, the management of RB patients depends on tumor stage at diagnosis. Enucleation is the therapeutic option for those with large unilateral tumors and no family history of disease (60-70% of all RB patients). In a subset of these patients, enucleation is followed by adjuvant chemotherapy to reduce the risks of tumor recurrence and metastasis. For bilateral RB cases, enucleation of the most affected eye is followed by systemic chemotherapy to the other eye. Despite these therapies, 30% of bilateral and 15% of unilateral (15%) cases, experience tumor recurrence defined by formation of new tumors within the first 1 to 3 years after diagnosis and enucleation. The goal of this project is to identify molecular markers associated with tumor recurrence risk. We hypothesize that a comprehensive study of genomic instability within RB tumors by using whole genome SNP (single nucleotide polymorphism) based chromosomal copy number analysis and correlating this information with microarray based gene expression studies, will help to identify molecular markers that will be informative of tumor biology and recurrence risk. To rigorously test this hypothesis, we propose a set of complementary specific aims, which will make use of genomic techniques to analyze RB tumor samples with associated clinical data. Specific Aim 1 To obtain a profile of loss and gain of chromosomal regions sampled from the whole genome of a RB tumor that can be used to predict recurrence of the disease. Specific Aim 2 To obtain the profile of gene expression of RB tumors that can identify molecular markers that will predict the risk of recurrence of the disease. Specific Aim 3 To combine the data obtained from Aims 1 and 2 to build a molecular classifier for RB recurrence. The outcome of this project will be high resolution whole genome profiles of a set of well-annotated RB tumors. This data can be analyzed to give a better understanding of the underlying biology of RB tumorigenesis. In many other types of cancer, these profiles have been used to identify class specific molecular signatures that can predict risk of tumor recurrence. The identification of molecular signatures will translate to improved management of future pediatric patients with RB, save the vision and change the quality of life of affected children and their families. Retinoblastoma (RB) is a childhood ocular tumor that can lead to blindness and death if not diagnosed early. The objective of this project is to facilitate the management of patients with RB, based on a better understanding of the molecular etiology of RB tumor initiation, progression and recurrence risk. To this end we will utilize new powerful high- resolution genomic profiling technologies to measure both chromosomal aberrations and gene expression levels in different classes of RB tumors. This will allow us to identify molecular signatures associated with risk of RB recurrence.