title: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  This signature may offer new insights into identifying new targets and therapies required to overcome the acquired resistance of gastric cancer to CF.
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors.forename: Hark Kyun
authors.initials: HK
authors.lastname: Kim
authors.forename: Il Ju
authors.initials: IJ
authors.lastname: Choi
authors.forename: Chan Gyoo
authors.initials: CG
authors.lastname: Kim
authors.forename: Hee Sung
authors.initials: HS
authors.lastname: Kim
authors.forename: Akira
authors.initials: A
authors.lastname: Oshima
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Michalowski
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Green
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
chemical_list: D002945:Cisplatin; D005472:Fluorouracil