Abstract LB-314: Whole exome sequencing analyses of gastric cancers reveal two distinct genomic alteration patterns with implications in drug sensitivity
Authors: Peille Anne-Lise , Wong Swee-Seong , Kiefer Florian , Zeitouni Bruno , Maier Armin , Foucault Frederic , Kees Tim , Vuaroqueaux Vincent , Aggarwal Amit , Reinhard Christoph , Fiebig Heinz Herbert 
Published: May 2015

Abstract
Gastric cancer is the fourth most common cancer diagnosed and the second most frequent cause of cancer-related death worldwide. Multiple factors can contribute to the development of gastric cancer, including H. pylori infection, dietary behaviour and life style, possibly resulting in distinct cancer subtypes with different drug sensitivity profiles. In the present study we searched for gastric cancer mutation patterns in the dataset of the “The Cancer Genome Atlas” (TCGA) and in our collection of patient derived xenografts (PDX). In a second part, we evaluated gene alteration patterns for their implications for drug sensitivity.
In both TCGA and our PDX datasets, Whole Exome Sequencing analyses revealed two subsets of gastric tumors characterized by specific mutation signatures, with different types and numbers of genomic alterations. The first subset (60% and 75% of samples) contained lower levels of mutations and was characterized by increased numbers of large chromosomal rearrangements resulting in gene loss or amplifications. The second subset of tumors (25%-40% of samples) revealed higher levels of mutations that were predominantly nucleic acid substitutions and small indels linked to mismatch repair genes including MLH1 or MSH3 and to high microsatellite instability. In both subsets, the mutation spectrum was dominated by C&gt;T transitions with an increase of small indels in the subset of highly-mutated tumors.
At the gene level, the genes which were mutated in our gastric PDX collection overlapped to great extent with the mutations found in TCGA tumors, especially regarding the most frequently mutated genes. In the first subset, high levels of gene amplifications and deletions were found, including growth factor receptor amplifications in EGFR and HER2. Furthermore, the mutation frequency in genes associated with drug resistance such as KRAS was decreased. The tumors with growth factor receptor amplification responded consistently to therapies such as Cetuximab or Trastuzumab. In contrast, an increased frequency of mutations in oncogenes and tumor suppressors, including KRAS (n=5/10), PIK3CA (n=5/10) and PTEN (n=7/10), was found in the second subset. The mutational profile of these tumors suggest the use of compounds targeting downstream molecules, such as PIK3CA, or targeting effectors of DNA repair, such as PARP, for anti-cancer therapy. Of note, no association was found between the mutation groups and sensitivity to chemotherapeutic agents such as 5FU, Cisplatin or Paclitaxel.
In conclusion, we identified two subsets of gastric tumors both in the TCGA dataset and in our collection of PDX models, characterized by distinct genomic alteration profiles suggesting different therapeutic approaches. Currently, we are assessing drug sensitivity profiles within the two subsets in our PDX models.
Citation Format: Anne-Lise Peille, Swee-Seong Wong, Florian Kiefer, Bruno Zeitouni, Armin Maier, Frederic Foucault, Tim Kees, Vincent Vuaroqueaux, Amit Aggarwal, Christoph Reinhard, Heinz Herbert Fiebig. Whole exome sequencing analyses of gastric cancers reveal two distinct genomic alteration patterns with implications in drug sensitivity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-314. doi:10.1158/1538-7445.AM2014-LB-314