Abstract
Abstract Background: The treatment of advanced gastric cancer remains a challenge for the clinical oncologist. Once distant metastases are present, median survival is around one year with the most active chemotherapeutic regimen. Besides the recent approval of trastuzumab in combination with chemotherapy, thus far no other molecular targeted agents have been approved for the treatment of this disease. There is an urgent need to improve selection of effective treatment for individual patients. A potentially promising approach for selecting active antitumor agents in individual patients could be the evaluation of tumor DNA for amplifications of genes coding for drug targets. Material and Methods: 183 primary gastric adenocarcinomas were analyzed by genome wide array Comparative Genomic Hybridization (arrayCGH) using microarrays consisting of 5000 BAC clones. High level amplifications were defined as a minimum of 2 consecutive clones showing a log2 tumor to normal ratio of > 1. Amplification frequencies for each BAC clone were calculated among the 183 tumors, and genes located within the amplicons were identified by using the RefSeq genes in the UCSC genome browser, version hg16/NCBI34. Drug target genes were selected with Ingenuity Pathway Analysis (IPA) and the Pharmacogenomics Knowledge Base (PharmGKB). Genes amplified in at least 4 patients (2%) were classified according to the mechanism of action of the drug interacting with this specific gene. Results: In 183 gastric cancers a mean number of 2.0 amplifications per tumor (range 0-21) was found. 167 genes out of more than 6000 at these loci were annotated as drug target genes by IPA, with 30 genes having an amplification frequency of at least 4 (2%). Most frequently amplified regions were located on chromosome 6, 8, 11, 16, 17 and 20. Genes for molecular targeting agents included VEGFA (6.5%), ERBB2 (6%), HSP90AB1 (5.5%) and EGFR (3.8%). Interestingly, also genes for non-anticancer agents, including HRH3 (10.4 %) and RARA (4.9%), and potential therapeutic targets such as TNFRSF4B (7.1%) were found. Conclusion: ArrayCGH analysis of a large series of gastric tumors revealed many non-randomly amplified gene loci, including substrates for targeted agents with potential antitumor activity in advanced gastric cancer. Moreover, targets of agents without established anticancer activity were identified as well. Our results provide a molecular rationale for the investigation of new treatment strategies in advanced gastric cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3941. doi:10.1158/1538-7445.AM2011-3941
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