Molecular and Genetic Analysis of Neuroendocrine Tumor Risk and Survival

神经内分泌肿瘤风险和生存的分子和遗传学分析

• 批准号: 8515971
• 负责人: Matthew H Kulke
• 金额: $ 55.1万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-06 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515971
• 关键词: 14q11; Apoptosis; Archives; Biology; Chromosomes; Chromosomes, Human, Pair 18; Clinical; Clinical Data; Clinical Management; DNA; Data; Databases; Diagnosis; Disease; Funding; Future; Genes; Genetic; Genetic Determinism; Genomics; Incidence; Individual; Inherited; K-Series Research Career Programs; Loss of Heterozygosity; Malignant Neoplasms; Molecular; Molecular Analysis; Molecular Genetics; National Cancer Institute; Neuroendocrine Tumors; Outcome; PECAM1 gene; PTEN gene; Pathologic; Pathway interactions; Patients; Populations at Risk; Prevalence; Prognostic Factor; Prognostic Marker; Proteins; Research Personnel; Research Priority; Resources; Risk; Risk Factors; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Small Intestinal Carcinoid Tumor; Specimen; Staging; Syndrome; TSC2 gene; United States; VEGFA gene; Variant; Vascular Endothelial Growth Factor Receptor-2; angiogenesis; design; disorder risk; genetic analysis; genetic variant; human FRAP1 protein; improved; mTOR Signaling Pathway; meetings; new therapeutic target; outcome forecast; pre-clinical; prognostic; repository; tumor; tumor growth

DESCRIPTION (provided by applicant): The incidence of neuroendocrine tumors is increasing, and the annual prevalence of these malignancies is estimated to exceed 100,000 individuals in the United States. Neuroendocrine tumors are rarely associated with inherited genetic syndromes; however, risk factors for the vast majority of "sporadic" neuroendocrine tumors have not been identified. Similarly, prognostic factors for these tumors are poorly understood. The identification of genetic and molecular prognostic factors for neuroendocrine tumors was identified as a key research priority at a National Cancer Institute summit meeting in September, 2007. Our proposed studies will leverage the resources of a large database of neuroendocrine tumor patients and biospecimens, developed by the PI during his prior K23 career development award. The database provides detailed clinical, pathologic, and outcome data, together with banked germline DNA and archived tumor specimens. Our aims are informed by recent preclinical and clinical data suggesting key roles for angiogenesis and mTOR signaling, as well as by a previous analysis of genomic aberrations in neuroendocrine tumors, performed by the PI. In Aim 1, we propose a two-stage candidate SNP approach to identify and then confirm genetic predictors of risk or survival in these pathways. In Aim 2, we propose to identify and validate immunohistochemical predictors of survival for in these same pathways. In Aim 3, we will assess the potential prognostic significance of chromosome 14q11 amplification or chromosome 18 LOH in small bowel carcinoid tumors. The results will inform our understanding of neuroendocrine tumor risk, prognosis, and biology. Our studies will also potentially identify at-risk populations and new therapeutic targets for this disease. Beyond the proposed aims, this database and specimen repository will allow for the rapid examination of future hypotheses as they emerge.

描述（由申请人提供）：神经内分泌肿瘤的发病率正在增加，在美国，这些恶性肿瘤的年患病率估计超过100，000例。神经内分泌肿瘤很少与遗传性遗传综合征相关;然而，绝大多数“散发性”神经内分泌肿瘤的危险因素尚未确定。同样，这些肿瘤的预后因素也知之甚少。神经内分泌肿瘤的遗传和分子预后因素的鉴定在2007年9月的国家癌症研究所峰会上被确定为一个关键的研究重点。我们提出的研究将利用PI在之前的K23职业发展奖期间开发的神经内分泌肿瘤患者和生物标本的大型数据库的资源。该数据库提供了详细的临床，病理和结果数据，以及库存的生殖系DNA和存档的肿瘤标本。我们的目的是根据最近的临床前和临床数据，表明血管生成和mTOR信号传导的关键作用，以及PI先前对神经内分泌肿瘤中基因组畸变的分析。在目标1中，我们提出了一种两阶段候选SNP方法来识别并确认这些途径中风险或生存的遗传预测因子。在目标2中，我们建议识别和验证这些相同途径中的生存预测因子。在目标3中，我们将评估染色体14 q11扩增或染色体18洛缺失在小肠类癌中的潜在预后意义。这些结果将为我们了解神经内分泌肿瘤的风险，预后和生物学提供信息。我们的研究还将潜在地确定这种疾病的高危人群和新的治疗靶点。除了提出的目标，这个数据库和标本库将允许快速检查未来的假设，因为他们出现。