Application of genomic approaches to classify retinoblastoma tumors

描述（由申请人提供）：视网膜母细胞瘤（RB）是一种儿童眼部肿瘤，如果没有早期诊断，可能导致失明和死亡。目前，RB患者的管理取决于诊断时的肿瘤分期。眼球摘除术是单侧大肿瘤且无家族病史患者的治疗选择（占所有RB患者的60-70%）。在这些患者的一个子集，眼球摘除术后辅助化疗，以减少肿瘤复发和转移的风险。对于双侧RB病例，对最受影响的眼睛进行眼球摘除术，然后对另一只眼睛进行全身化疗。尽管有这些治疗，30%的双侧和15%的单侧（15%）病例在诊断和摘除术后的前1至3年内发生肿瘤复发，定义为新肿瘤的形成。该项目的目标是确定与肿瘤复发风险相关的分子标志物。我们假设，通过使用基于全基因组SNP（单核苷酸多态性）的染色体拷贝数分析，并将此信息与基于基因表达研究的微阵列相关联，对RB肿瘤内基因组不稳定性进行全面研究，将有助于识别可提供肿瘤生物学和复发风险信息的分子标记物。为了严格检验这一假设，我们提出了一套互补的具体目标，这将利用基因组技术来分析RB肿瘤样本与相关的临床数据。具体目的1获得从RB肿瘤的全基因组取样的染色体区域的丢失和获得的概况，其可用于预测疾病的复发。具体目的2获得RB肿瘤的基因表达谱，以确定预测疾病复发风险的分子标志物。具体目标3将从目标1和2获得的数据联合收割机以建立RB复发的分子分类器。该项目的成果将是一组注释良好的RB肿瘤的高分辨率全基因组图谱。这些数据可以进行分析，以更好地了解RB肿瘤发生的基础生物学。在许多其他类型的癌症中，这些谱已被用于鉴定可预测肿瘤复发风险的类别特异性分子特征。分子特征的识别将有助于改善未来RB儿科患者的管理，挽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，如果没有早期诊断，可能导致失明和死亡。本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学的基础上，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分析技术来测量不同类型RB肿瘤中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.