Genome Discovery and Validation in Upper Gastrointestinal Carcinomas

上消化道癌基因组的发现和验证

• 批准号: 7513485
• 负责人: Adam Joel Bass
• 金额: $ 14.09万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7513485
• 关键词: Area; Automobile Driving; Bass; Biological Assay; Cancer Biology; Cancer cell line; Candidate Disease Gene; Carcinoma; Cell Line; Clinical; Collaborations; Collection; Colorectal Cancer; DNA; Data; Data Set; Development; Disease; Drug Delivery Systems; Esophageal Adenocarcinoma; Esophageal Squamous Cell Carcinoma; Esophageal carcinoma; Esophagus; Event; Freezing; Future; Gastric Adenocarcinoma; Gastrointestinal tract structure; Generations; Genes; Genetic; Genetic Identity; Genome; Genomics; Genotype; Goals; International; Intervention; Laboratories; Lead; Lesion; Link; Lung; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of esophagus; Measures; Medical Oncology; Modeling; Mutation; Numbers; Oncogenes; Pathogenesis; Patients; Phosphotransferases; Physicians; Primitive foregut structure; Protein Overexpression; Protein Tyrosine Kinase; Recurrence; Research; Research Personnel; Sampling; Scientist; Squamous cell carcinoma; Stomach; Stomach Carcinoma; Subgroup; Techniques; Technology; Therapeutic; Therapeutic Agents; Training; Upper digestive tract structure; Validation; Work; base; cancer care; density; follow-up; gastrointestinal; genotyping technology; improved; innovation; insight; novel; programs; repository; sample collection; skills; small hairpin RNA; tool; transcription factor; tumor; validation studies

DESCRIPTION (provided by applicant): As a physician trained in medical oncology, I aim to develop the skills necessary to allow me to become an independent translational physician-scientist. The goal of this proposal is to identity the genetic basis for carcinomas of the stomach and esophagus with the eventual hope to develop improved treatments for these disorders based on genetic insights into disease pathogenesis. The sponsor of this application, Matthew Meyerson, has developed techniques to study genomic aberrations in cancer using high-density SNP arrays and other novel sequencing and genotyping technologies. As a basis for genomic discovery and characterization we have built a collection of DNA samples derived from fresh-frozen gastric and esophageal carcinomas and will have access to >100 gastrointestinal carcinoma cell lines. Using these arrays, our early data shows frequent recurrent genomic aberrations in gastric and esophageal carcinomas. Many of these aberrations target tyrosine kinases, suggesting that subgroups of patients with these diseases may benefit from treatments with targeted inhibition of these kinases. We have also identified a novel amplification in squamous aerodigestive carcinomas and have initiated functional studies to validate this new potential oncogene. The Specific Aims are: 1. To generate and analyze high-density SNP array data from over 300 carcinomas and cell lines of the stomach and esophagus to identify regions of amplification and deletion. 2. To genotype a panel of over 300 gastric and esophageal carcinoma primary samples and cell lines for over 1000 annotated mutations in 83 cancer-associated genes and build a collection of genomically annotated cell lines for use in validation studies. 3. To validate a new putative oncogene in squamous aerodigestive carcinomas and subsequently validate other candidate genes in selected copy-number alterations in gastric and esophageal carcinomas. Relevance: This project will use genomic tools to identify critical genetic alterations in a large panel of gastric and esophageal cancer samples and will use more traditional laboratory techniques to follow-up candidate genes identified through genomic studies. Through this work, we have the potential to identify and validate critical drug targets in these diseases. Results of these studies could directly lead to development of improved therapeutic strategies for patients with these deadly malignancies.

描述（由申请人提供）：作为一名接受过肿瘤内科培训的医生，我的目标是培养必要的技能，使我能够成为一名独立的转化医师科学家。该提案的目标是确定胃癌和食道癌的遗传基础，最终希望根据对疾病发病机制的遗传见解开发出针对这些疾病的改进治疗方法。该申请的发起人 Matthew Meyerson 开发了利用高密度 SNP 阵列和其他新颖的测序和基因分型技术来研究癌症基因组畸变的技术。作为基因组发现和表征的基础，我们建立了来自新鲜冷冻胃癌和食道癌的 DNA 样本集合，并将获得超过 100 种胃肠癌细胞系。使用这些阵列，我们的早期数据显示胃癌和食道癌中频繁出现的基因组畸变。许多这些畸变都针对酪氨酸激酶，这表明患有这些疾病的患者亚群可能受益于这些激酶的靶向抑制治疗。我们还在鳞状呼吸消化癌中发现了一种新的扩增，并启动了功能研究来验证这种新的潜在癌基因。 具体目标是： 1. 生成并分析来自 300 多种胃和食道癌和细胞系的高密度 SNP 阵列数据，以确定扩增和缺失区域。 2. 对 300 多个胃癌和食管癌原代样本和细胞系的 83 个癌症相关基因的 1000 多个注释突变进行基因分型，并建立基因组注释细胞系集合以用于验证研究。 3. 验证鳞状呼吸消化癌中的一种新的假定癌基因，并随后验证胃癌和食管癌中选定拷贝数改变中的其他候选基因。 相关性：该项目将使用基因组工具来识别大量胃癌和食道癌样本中的关键遗传改变，并将使用更传统的实验室技术来跟踪通过基因组研究确定的候选基因。通过这项工作，我们有可能识别和验证这些疾病的关键药物靶点。这些研究的结果可能直接导致为患有这些致命恶性肿瘤的患者开发改进的治疗策略。