Genome Discovery and Validation in Upper Gastrointestinal Carcinomas

描述（由申请人提供）：作为一名接受过医学肿瘤学培训的医生，我的目标是发展必要的技能，使我成为一名独立的翻译医生-科学家。该提案的目标是确定胃癌和食管癌的遗传基础，并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。本申请的申办者Matthew Meyerson开发了使用高密度SNP阵列和其他新型测序和基因分型技术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，我们已经建立了一个来自新鲜冷冻胃癌和食管癌的DNA样品的集合，并将获得>100个胃肠道癌细胞系。使用这些阵列，我们的早期数据显示在胃癌和食管癌中频繁复发的基因组畸变。这些畸变中的许多靶向酪氨酸激酶，表明患有这些疾病的患者亚组可能受益于靶向抑制这些激酶的治疗。我们还发现了一种新的扩增在鳞状呼吸消化道癌，并已启动功能研究，以验证这一新的潜在的癌基因。 具体目标是： 1.生成并分析来自300多个胃癌和食管癌细胞系的高密度SNP阵列数据，以识别扩增和缺失区域。 2.对一组300多个胃癌和食管癌原代样本和细胞系进行83个癌症相关基因中1000多个注释突变的基因分型，并建立一组基因组注释细胞系用于验证研究。 3.验证一种新的呼吸消化道鳞状细胞癌的假定癌基因，并随后验证其他候选基因在胃和食管癌中的选择性拷贝数改变。 相关性：该项目将使用基因组工具来确定一大组胃癌和食管癌样本中的关键遗传变异，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中的关键药物靶标。这些研究的结果可能直接导致这些致命恶性肿瘤患者的治疗策略的改进。

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.