An evaluation of microRNA signature and response of patients with gastric cancer to cisplatin and fluorouracil.

Abstract

4062 Background: In previous miRNA microarray studies in gastric cancer, adjacent non-tumor tissue was used as the control as opposed to tissue from healthy volunteers. Also, most of previous studies attempting to identify miRNA predictors of clinical chemoresistance in cancer have examined only individual miRNAs. Very few high-throughput microarray analyses have been performed to identify miRNA expression signatures predictive of chemotherapy resistance in metastatic solid tumor patients. 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: Endoscopic 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 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) after CF. Results: A signature distinguishing gastric cancer from normal stomach epithelium was identified. Fifty-eight miRNAs were significantly correlated with TTP of 82 cancer patients (P<0.05). Prominent among upregulated chemosensitive miRNAs were miRNAs associated with apoptosis. 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 8 pre-treatment samples were correctly predicted as low-risk, whereas samples from the post-treatment, chemoresistant state were enriched for the 58 miRNA signature, suggesting that selection for the expression of these miRNAs occurred as chemoresistance developed. Conclusions: This study identified a miRNA expression signature that distinguishes gastric cancer from normal stomach epithelium from healthy volunteers, and a chemoreresistance miRNA expression signature that is correlated with TTP after CF, although limited by the small sample size of the validation set.