Deep sequencing of gastric carcinoma reveals somatic mutations relevant to personalized medicine
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RESEARCH
Open Access
Deep sequencing of gastric carcinoma reveals somatic mutations relevant to personalized medicine Joanna D Holbrook1,2*, Joel S Parker3, Kathleen T Gallagher4, Wendy S Halsey4, Ashley M Hughes4, Victor J Weigman3, Peter F Lebowitz1 and Rakesh Kumar1
Abstract Background: Globally, gastric cancer is the second most common cause of cancer-related death, with the majority of the health burden borne by economically less-developed countries. Methods: Here, we report a genetic characterization of 50 gastric adenocarcinoma samples, using affymetrix SNP arrays and Illumina mRNA expression arrays as well as Illumina sequencing of the coding regions of 384 genes belonging to various pathways known to be altered in other cancers. Results: Genetic alterations were observed in the WNT, Hedgehog, cell cycle, DNA damage and epithelial-tomesenchymal-transition pathways. Conclusions: The data suggests targeted therapies approved or in clinical development for gastric carcinoma would be of benefit to ~22% of the patients studied. In addition, the novel mutations detected here, are likely to influence clinical response and suggest new targets for drug discovery.
Background Despite recent decline of mortality rates from gastric cancer in North America and in most of Northern and Western Europe, stomach cancer remains one of the major causes of death worldwide and is common in Japan, Korea, Chile, Costa Rica, Russian Federation and other countries of the former soviet union [1]. Despite improvements in treatment modalities and screening, the prognosis of patients with gastric adenocarcinoma remains poor [2]. To understand the pathogenesis and to develop new therapeutic strategies, it is essential to dissect the molecular mechanisms that regulate the progression of gastric cancer. In particular, the oncogenic mechanisms which can be targeted by personalized medicine. The term “oncogene addiction” to describe cancer cells highly dependent on a given oncogene or oncogenic pathway was introduced by Weinstein [3,4]. The concept underscores the development of targeted * Correspondence: [email protected] 1 Cancer Research, Oncology R&D, Glaxosmithkline R&D, 1250 Collegeville Road, Collegeville, USA Full list of author information is available at the end of the article
therapies which attempt to inactivate an oncogene, critical to survival of cancer cells whilst sparing normal cells which are not similarly addicted. Several oncogenes activated at high frequency in other cancers have also been shown to be mutated in gastric cancer. It follows that marketed therapeutics targeting these oncogenes would effectively treat a proportion of gastric carcinomas, either as single agents or in combination. In January 2010, trastuzumab was approved in combination with chemotherapy for the first-line treatment of ERBB2-positive advanced and metastatic gastric cancer. Trastuzumab is the first targeted agent to be approved for the treatment of gastric carcinoma and an increase of 12.8% in response rate was seen with ad
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