Discovery of Chromosome Arm 11q Tumor Suppressor Genes in Neuroblastoma

神经母细胞瘤中染色体臂 11q 抑癌基因的发现

• 批准号: 7467944
• 负责人: EDWARD F ATTIYEH
• 金额: $ 13.93万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7467944
• 关键词: 11q; Area; Behavior; Biological; Biological Models; Breast Carcinoma; Candidate Disease Gene; Cell Adhesion; Cell Line; Cervix Uteri; Child; Chromosome Arm; Chromosome Transfer; Chromosomes, Human, Pair 11; Classification; Clinical; Colon; Complement; Data; Development; Disease Outcome; Environment; Epigenetic Process; Funding; Genes; Genetic; Genomics; Genus Cola; Goals; Human; Immunoglobulins; In Vitro; Incidental Findings; Invasive; Loss of Heterozygosity; Lung; MYCN gene; Malignant Neoplasms; Maps; Mediating; Mentors; Modeling; Modification; Mutation; Neuroblastoma; Oncogenic; Operative Surgical Procedures; Outcome; Ovary; Pathogenesis; Pathway interactions; Patients; Pediatric Hospitals; Pennsylvania; Phenotype; Philadelphia; Physicians; Primary Neoplasm; Principal Investigator; Proteins; Research; Research Personnel; Research Training; Resolution; Resources; Risk; Scientist; Single Nucleotide Polymorphism; Stratification; Suppressor Genes; System; Training Programs; Tumor Suppressor Genes; Tumorigenicity; Universities; Variant; Work; cancer genetics; cell behavior; cell growth; clinically significant; drug development; functional genomics; improved; in vivo; melanoma; member; mutant; neoplastic cell; novel strategies; novel therapeutics; prognostic; programs; therapeutic target; transcriptomics; tumor; tumorigenic

DESCRIPTION (provided by applicant): Neuroblastoma remains one of the deadliest cancers in children. Understanding the genetic differences between low- and high-risk neuroblastomas is critical to improving our prognostic abilities and to providing therapeutic targets. Most invasive neuroblastomas are defined either by MYCN amplification (40%) or 11q loss of heterozygosity (30%), but rarely do these occur in the same tumor. The clinical significance of 11q loss strongly suggests that one or more neuroblastoma tumor suppressor genes are located in this region. Notably, there have been no bona fide neuroblastoma suppressor genes discovered. We hypothesize that functional inactivation of at least two genes located at 11q is required for the development of an aggressive neuroblastoma phenotype in the absence of oncogenic activation of MYCN. This proposal seeks to discover 11q neuroblastoma suppressor genes by achieving the following specific aims: (1) identify 11q regions associated with aggressive neuroblastoma; (2) identify relevant 11q genes using functional and genetic approaches; and (3) confirm the biological relevance of candidate 11q tumor suppressor genes. Chromosome arm 11q aberrations are also present in many other human cancers, suggesting that any 11q neuroblastoma suppressor gene might also be involved in the pathogenesis of other malignancies. This proposal lays out a 5-year research and training program with the ultimate goal to transition the principal investigator to an independent R01-funded physician-scientist. His mentors and advisors are leaders in the field of neuroblastoma research and cancer genetics. He will take advantage of the ample resources of his environment, both at the Children's Hospital of Philadelphia and the University of Pennsylvania. Relevance: Increases in treatment intensity in neuroblastoma have resulted in only modest improvements in survival; it is clear that new approaches are needed. We propose a systematic approach to discovering tumor suppressor genes on chromosome arm 11q, which is often deleted in aggressive neuroblastoma. This will directly impact the treatment of children with neuroblastoma by improving our prognostic ability and providing new avenues for drug development.

描述（由申请人提供）：神经母细胞瘤仍然是儿童中最致命的癌症之一。了解低风险和高风险神经母细胞瘤之间的遗传差异对于提高我们的预后能力和提供治疗靶点至关重要。大多数侵袭性神经母细胞瘤是通过 MYCN 扩增 (40%) 或 11q 杂合性缺失 (30%) 来定义的，但这些情况很少发生在同一肿瘤中。 11q 缺失的临床意义强烈表明一个或多个神经母细胞瘤肿瘤抑制基因位于该区域。值得注意的是，尚未发现真正的神经母细胞瘤抑制基因。我们假设，在没有 MYCN 致癌激活的情况下，侵袭性神经母细胞瘤表型的发展需要位于 11q 的至少两个基因的功能失活。该提案旨在通过实现以下具体目标来发现11q神经母细胞瘤抑制基因：（1）识别与侵袭性神经母细胞瘤相关的11q区域； (2) 使用功能和遗传学方法鉴定相关的11q基因； (3) 确认候选11q抑癌基因的生物学相关性。染色体臂 11q 畸变也存在于许多其他人类癌症中，这表明任何 11q 神经母细胞瘤抑制基因也可能参与其他恶性肿瘤的发病机制。 该提案制定了一项为期 5 年的研究和培训计划，最终目标是将主要研究者转变为由 R01 资助的独立医师科学家。他的导师和顾问是神经母细胞瘤研究和癌症遗传学领域的领导者。他将利用费城儿童医院和宾夕法尼亚大学丰富的环境资源。 相关性：神经母细胞瘤治疗强度的增加仅导致生存率略有改善；显然需要新的方法。我们提出了一种系统方法来发现染色体臂 11q 上的肿瘤抑制基因，该基因在侵袭性神经母细胞瘤中经常被删除。这将通过提高我们的预后能力并为药物开发提供新途径，直接影响儿童神经母细胞瘤的治疗。