Genome Discovery and Validation in Upper Gastrointestinal Carcinomas

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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.