Abstract 4284: Embryonic stem cell signature is enriched in the acquired resistance signature of gastric cancer patients to cisplatin/fluorouracil, and segregates newly diagnosed patients according to treatment outcome
Authors: Kim Hark K. , Choi Il J. , Kim Chan G. , Oshima Akira , Michalowski Aleksandra , Green Jeffrey E. 
Published: February 2011

Although cytotoxic chemotherapy remains the primary treatment option for metastatic cancer patients, even clinical responders ultimately develop the acquired resistance to chemotherapy. We hypothesized that identifying transcriptional alterations associated with acquired chemotherapy resistance from pre- and post-biopsy samples from the same patient would uncover potential molecular pathways involved in treatment failure. The serial collection of solid tumor samples from the same patients has been extremely difficult, but gastric cancer provides a unique opportunity since repeated endoscopies may be performed.

We performed a prospective, high-throughput transcriptional profiling study using endoscopic biopsy samples from metastatic gastric cancer patients treated with cisplatin and fluorouracil (CF) combination chemotherapy at National Cancer Center in Korea. Twenty-two patients who initially responded to CF (with partial response according to WHO criteria) were biopsied a second time after they developed resistance to CF (at progressive disease according to WHO criteria). An acquired chemotherapy resistance signature was identified by analyzing the DNA microarray (U133A) expression profiles from the matched pre- and post-CF treated samples. The similarity of the acquired resistance signature to published embryonic stem (ES) cell signatures was tested using gene set comparison algorithms of BRB-ArrayTools.

The acquired resistance gene signature was enriched for genes over-expressed in the published ES cell signature (defined by genes over-expressed in at least 5/20 human ES cells profiling studies) (LS P value&lt;0.005). When this ES cell signature was modified to exclude genes listed in the Proliferation category of Gene Ontology and the proliferation cluster of breast cancer, the overlap between this amended ES expression set and our acquired resistance signature was still statistically significant. Importantly, genes overlapping between the ES cell signatures and the acquired resistance signature could segregate 101 newly-diagnosed metastatic gastric cancer patients according to progression-free survival and overall survival after CF chemotherapy (adjusted P values, 0.011 and 0.034, respectively).

Thus, ES cell signature is enriched in our acquired resistance signature to CF, and may represent the core gene expression signature for clinical chemoresistance. To our knowledge, this work is the first study demonstrating the enrichement of ES cell signature in clinical specimens collected at the time of acquired resistance to cytotoxic chemotherapy. Genes contained in our acquired resistance signature may serve as clinically relevant molecular target candidates (supported in part by NIH Intramural Program, CCR, NCI; and by Korean NCC Grant 0910570).

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4284.