Correlative Genetic Markers in Childhood Hepatoblastoma

儿童肝母细胞瘤的相关遗传标记

• 批准号: 7471992
• 负责人: GAIL ELIZABETH TOMLINSON
• 金额: $ 25.18万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-29 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7471992
• 关键词: 1q21; Adjuvant Chemotherapy; Child; Childhood; Chromosomal translocation; Chromosomes; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 2; Class; Clinical; Clinical Data; Cluster Analysis; Common Neoplasm; Correlative Study; Cytotoxic Chemotherapy; Data; Data Analyses; Databases; Development; Diagnostic; Diagnostic Neoplasm Staging; Disease Clusterings; Excision; Family; Future; Genes; Genetic; Genetic Markers; Genetic Materials; Genetic Predisposition to Disease; Genome; Genomics; Goals; Hepatoblastoma; Infant; Lead; Link; Liver; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of liver; Methodology; Mutation; Non-Malignant; Numbers; Oligonucleotide Microarrays; Oligonucleotides; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pattern; Phenotype; Pilot Projects; Play; Prognostic Marker; Proteins; Protocols documentation; Public Health; Recurrence; Reporting; Research Personnel; Resources; Risk; Role; Sampling; Series; Specimen; Stratification; Techniques; Tissues; Translocation Breakpoint; Treatment Protocols; Trisomy; Trisomy 2; Tumor Tissue; Tumor stage; Unresectable; Upper arm; Variant; base; chemotherapy; chromosome 1 loss; clinically relevant; comparative genomic hybridization; interest; novel; prospective; response; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Characterization of genetic changes in cancer, particularly chromosomal translocations, has led to a better understanding of tumorigenic pathways and also has served to develop diagnostic and prognostic markers which allow stratification of treatment regimens by risk groups. In addition, characterization of chromosomal translocations and their gene products have led to the development of novel targeted therapies that are much less toxic than conventional cytotoxic chemotherapy. Hepatoblastoma, the most common tumor of the liver in children, is characterized by specific chromosomal changes, the most common being trisomy of chromosomes 2, 8 and 20. Hepatoblastoma is also characterized by a family of translocations involving a common breakpoint at chromosome 1q12. Interestingly, the first four tumors we reported which demonstrated a similar, recurring translocation, t(1;4)(q12;q34) were all observed in high-stage tumors. Within our large series of karyotypes, frequent translocation are observed in which the long arm of chromosome 1 is translocated to other chromosomal loci, all with a resultant gain of genetic material on chromosome 1 and loss of genetic material on the reciprocal chromosome. We have recently determined using oligonucleotide array comparative genomic hybridization (oaCGH) that the translocation breakpoint lies in the vicinity of NOTCH2, a gene involved in liver development and specifically in hepatoblast differentiation. NOTCH2 is expressed at high levels in hepatoblastoma tumor samples and at low levels in non-malignant liver tissue suggesting that it may play an important role in tumorigenesis. The overall goal of this project is to correlate our observed chromosomal changes in hepatoblastoma with clinical features. Specifically, we hypothesize that chromosomal trisomies are associated with a worse outcome. Likewise we hypothesize that tumors which have the observed translocations involving NOTCH2 have a more aggressive phenotype. Utilizing oaCGH, chromosomal copy number changes will be analyzed in our unique resource of 220 hepatoblastoma tumor tissues ascertained as part of cooperative group protocols and annotated with clinical data. Using a series of very finely tiled oligonucleotides, we will characterize the breakpoint on chromosome 1. Class discovery methodology will be used to characterize patterns of multiple copy number changes among multiple tumor samples. Realization of these aims will lead to the development of markers that will help predict outcome and thereby serve to guide future therapies, either in the stratification into risk groups or in the development of novel therapies. A product of this project will be a powerful databank of genomic copy number changes which will be made available to researchers as a resource to further the understanding of genetic etiologies of liver tumorigenesis in children. In addition, this pilot study will generate preliminary data to plan prospective treatment studies with correlative genetic studies. 7. PUBLIC HEALTH RELEVANCE: Hepatoblastoma is a cancer of the liver that develops in infants and young children and is often difficult to successfully treat. Hepatoblastoma tumor tissues are characterized by well- defined chromosome changes, the clinical relevance of which is unknown. This study will examine chromosome changes in 220 hepatoblastoma tumor specimens and will determine if these alterations can be used to predict patient outcome and hence guide future therapies.

描述（由申请方提供）：癌症遗传变化的表征，特别是染色体易位，已导致对致瘤途径的更好理解，并且还用于开发诊断和预后标志物，其允许按风险组对治疗方案进行分层。此外，染色体易位及其基因产物的表征已经导致了比常规细胞毒性化疗毒性小得多的新型靶向疗法的开发。肝母细胞瘤是儿童中最常见的肝脏肿瘤，其特征在于特定的染色体变化，最常见的是染色体2、8和20的三体。肝母细胞瘤的特征还在于涉及染色体1 q12处的共同断点的易位家族。有趣的是，我们报告的前四个肿瘤表现出类似的复发性易位，t（1;4）（q12;q34），都是在高分期肿瘤中观察到的。在我们的一系列核型中，经常观察到易位，其中1号染色体的长臂易位到其他染色体位点，所有这些都导致1号染色体上遗传物质的获得和相互染色体上遗传物质的损失。我们最近确定使用寡核苷酸阵列比较基因组杂交（oaCGH），易位断点位于附近的NOTCH 2，参与肝脏发育，特别是在肝细胞分化的基因。NOTCH 2在肝母细胞瘤肿瘤样品中以高水平表达，而在非恶性肝组织中以低水平表达，这表明它可能在肿瘤发生中起重要作用。本项目的总体目标是将我们观察到的肝母细胞瘤染色体变化与临床特征相关联。具体来说，我们假设染色体三体与更差的结果相关。同样地，我们假设具有所观察到的涉及NOTCH 2的易位的肿瘤具有更具侵袭性的表型。利用oaCGH，染色体拷贝数的变化将在我们独特的220例肝母细胞瘤肿瘤组织资源中进行分析，这些组织是合作组方案的一部分，并附有临床数据。使用一系列非常精细平铺的寡核苷酸，我们将表征1号染色体上的断裂点。类别发现方法将用于表征多个肿瘤样本中多个拷贝数变化的模式。这些目标的实现将导致标记物的发展，这些标记物将有助于预测结果，从而指导未来的治疗，无论是在风险组的分层还是在新疗法的开发中。该项目的一个产品将是一个强大的基因组拷贝数变化的数据库，将提供给研究人员作为进一步了解儿童肝脏肿瘤发生的遗传病因学的资源。此外，这项试点研究将产生初步数据，以计划与相关遗传研究的前瞻性治疗研究。7.公共卫生相关性：肝母细胞瘤是一种在婴儿和幼儿中发展的肝脏癌症，并且通常难以成功治疗。肝母细胞瘤肿瘤组织的特征在于明确的染色体变化，其临床相关性尚不清楚。这项研究将检查220例肝母细胞瘤肿瘤标本的染色体变化，并确定这些变化是否可用于预测患者的预后，从而指导未来的治疗。