Dataset Information

A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.

ABSTRACT:

Background

We initiated a prospective trial to identify transcriptional alterations associated with acquired chemotherapy resistance from pre- and post-biopsy samples from the same patient and uncover potential molecular pathways involved in treatment failure to help guide therapeutic alternatives.

Methodology/principal findings

A prospective, high-throughput transcriptional profiling study was performed using endoscopic biopsy samples from 123 metastatic gastric cancer patients prior to cisplatin and fluorouracil (CF) combination chemotherapy. 22 patients who initially responded to CF were re-biopsied after they developed resistance to CF. An acquired chemotherapy resistance signature was identified by analyzing the gene expression profiles from the matched pre- and post-CF treated samples. The acquired resistance signature was able to segregate a separate cohort of 101 newly-diagnosed gastric cancer patients according to the time to progression after CF. Hierarchical clustering using a 633-gene acquired resistance signature (feature selection at P<0.01) separated the 101 pretreatment patient samples into two groups with significantly different times to progression (2.5 vs. 4.7 months). This 633-gene signature included the upregulation of AKT1, EIF4B, and RPS6 (mTOR pathway), DNA repair and drug metabolism genes, and was enriched for genes overexpressed in embryonic stem cell signatures. A 72-gene acquired resistance signature (a subset of the 633 gene signature also identified in ES cell-related gene sets) was an independent predictor for time to progression (adjusted P = 0.011) and survival (adjusted P = 0.034) of these 101 patients.

Conclusion/significance

This signature may offer new insights into identifying new targets and therapies required to overcome the acquired resistance of gastric cancer to CF.

SUBMITTER: Kim HK

PROVIDER: S-EPMC3041770 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Publications

A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.

Kim Hark Kyun HK Choi Il Ju IJ Kim Chan Gyoo CG Kim Hee Sung HS Oshima Akira A Michalowski Aleksandra A Green Jeffrey E JE

PloS one 20110218 2

<h4>Background</h4>We initiated a prospective trial to identify transcriptional alterations associated with acquired chemotherapy resistance from pre- and post-biopsy samples from the same patient and uncover potential molecular pathways involved in treatment failure to help guide therapeutic alternatives.<h4>Methodology/principal findings</h4>A prospective, high-throughput transcriptional profiling study was performed using endoscopic biopsy samples from 123 metastatic gastric cancer patients p ...[more]

PMID: 21364753

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Project description:BackgroundIt is a major clinical challenge to predict which patients, with advanced stage head and neck squamous cell carcinoma, will not exhibit a reduction in tumor size following induction chemotherapy in order to avoid toxic effects of ineffective chemotherapy and delays for instituting other therapeutic options. Further, it is of interest to know to what extent a gene signature, which identifies patients with tumors that will not respond to a particular induction chemotherapy, is applicable when additional chemotherapeutic agents are added to the regimen.Methodology/principal findingsTo identify genes that predict tumor resistance to induction with cisplatin/5-fluorouracil (PF) or PF and a taxane, we analyzed patient tumor biopsies with whole genome microarrays and quantitative reverse transcriptase-PCR (TLDA) cards. A leave one out cross-validation procedure allowed evaluation of the prediction tool. A ten-gene microarray signature correctly classified 12/13 responders and 7/10 non-responders to PF (92% specificity, 82.6% accuracy). TLDA analysis (using the same classifier) of the patients correctly classified 12/12 responders and 8/10 non-responders (100% specificity, 90.9% accuracy). Further, TLDA analysis correctly predicted the response of 5 new patients and, overall, 12/12 responders and 13/15 non-responders (100% specificity, 92.6% accuracy). The protein products of the genes constituting the signature physically associate with 27 other proteins, involved in regulating gene expression, constituting an interaction network. In contrast, TLDA-based prediction (with the same gene signature) of responses to induction with PF and either of two taxanes was poor (0% specificity, 25% accuracy and 33.3% specificity, 25% accuracy).Conclusions/significanceSuccessful transfer of the microarray-based gene signature to an independent, PCR-based technology suggests that TLDA-based signatures could be a useful hospital-based technology for determining therapeutic options. Although highly specific for tumor responses to PF induction, the gene signature is unsuccessful when taxanes are added. The results illustrate the subtlety in developing "personalized medicine".

Dataset Information

A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.

Background

Methodology/principal findings

Conclusion/significance

Publications

A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.

Similar Datasets

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