Genome Discovery and Validation in Upper Gastrointestinal Carcinomas

描述（由申请人提供）：作为一名接受过肿瘤医学培训的内科医生，我的目标是培养必要的技能，使我成为一名独立的转化内科医生-科学家。这项提议的目标是确定胃癌和食道癌的遗传基础，并最终希望基于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。这项申请的发起人马修·迈耶森（Matthew Meyerson）已经开发了使用高密度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。作为基因组发现和鉴定的基础，我们已经建立了从新鲜冷冻的胃癌和食管癌中提取的DNA样本集合，并将获得bbbb100胃肠道癌细胞系。使用这些阵列，我们的早期数据显示胃癌和食管癌中经常出现复发性基因组畸变。许多这些畸变靶向酪氨酸激酶，这表明这些疾病的亚组患者可能受益于靶向抑制这些激酶的治疗。我们还在鳞状气消化癌中发现了一种新的扩增基因，并启动了功能研究来验证这种新的潜在致癌基因。

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.