title: miRNA signature associated with outcome of gastric cancer patients following chemotherapy.
abstract: BACKGROUND
  Identification of patients who likely will or will not benefit from cytotoxic chemotherapy through the use of biomarkers could greatly improve clinical management by better defining appropriate treatment options for patients. microRNAs may be potentially useful biomarkers that help guide individualized therapy for cancer because microRNA expression is dysregulated in cancer. In order to identify miRNA signatures for gastric cancer and for predicting clinical resistance to cisplatin/fluorouracil (CF) chemotherapy, a comprehensive miRNA microarray analysis was performed using endoscopic biopsy samples.
  
  
  METHODS
  Biopsy samples were collected prior to chemotherapy from 90 gastric cancer patients treated with CF and from 34 healthy volunteers. At the time of disease progression, post-treatment samples were additionally collected from 8 clinical responders. miRNA expression was determined using a custom-designed Agilent microarray. In order to identify a miRNA signature for chemotherapy resistance, we correlated miRNA expression levels with the time to progression (TTP) of disease after CF therapy.
  
  
  RESULTS
  A miRNA signature distinguishing gastric cancer from normal stomach epithelium was identified. 30 miRNAs were significantly inversely correlated with TTP whereas 28 miRNAs were significantly positively correlated with TTP of 82 cancer patients (P<0.05). Prominent among the upregulated miRNAs associated with chemosensitivity were miRNAs known to regulate apoptosis, including let-7g, miR-342, miR-16, miR-181, miR-1, and miR-34. When this 58-miRNA predictor was applied to a separate set of pre- and post-treatment tumor samples from the 8 clinical responders, all of the 8 pre-treatment samples were correctly predicted as low-risk, whereas samples from the post-treatment tumors that developed chemoresistance were predicted to be in the high-risk category by the 58 miRNA signature, suggesting that selection for the expression of these miRNAs occurred as chemoresistance arose.
  
  
  CONCLUSIONS
  We have identified 1) a miRNA expression signature that distinguishes gastric cancer from normal stomach epithelium from healthy volunteers, and 2) a chemoreresistance miRNA expression signature that is correlated with TTP after CF therapy. The chemoresistance miRNA expression signature includes several miRNAs previously shown to regulate apoptosis in vitro, and warrants further validation.
authors: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
authors: Chang Hee
authors: CH
authors: Kim
authors: Hark K
authors: HK
authors: Kim
authors: R Luke
authors: RL
authors: Rettig
authors: Joseph
authors: J
authors: Kim
authors: Eunbyul T
authors: ET
authors: Lee
authors: Olga
authors: O
authors: Aprelikova
authors: Il J
authors: IJ
authors: Choi
authors: David J
authors: DJ
authors: Munroe
authors: Jeffrey E
authors: JE
authors: Green
mesh_terms: D000328:Adult; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D005753:Gastric Mucosa / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D035683:MicroRNAs; D002945:Cisplatin; D005472:Fluorouracil