title: A three-gene signature as potential predictive biomarker for irinotecan sensitivity in gastric cancer.
abstract: OBJECTIVE
  Personalized chemotherapy based on molecular biomarkers can maximize anticancer efficiency. We aim to investigate predictive biomarkers capable of predicting response to irinotecan-based treatment in gastric cancer.
  
  
  METHODS
  We examined gene expression of APTX, BRCA1, ERCC1, ISG15, Topo1 and methylation of SULF2 in formalin-fixed paraffin-embedded gastric cancer tissues from 175 patients and evaluated the association between gene expression levels or methylation status and in vitro sensitivity to irinotecan. We used multiple linear regression analysis to develop a gene-expression model to predict irinotecan sensitivity in gastric cancer and validated this model in vitro and vivo.
  
  
  RESULTS
  Gene expression levels of APTX, BRCA1 and ERCC1 were significantly lower in irinotecan-sensitive gastric cancer samples than those irinotecan-resistant samples (P<0.001 for all genes), while ISG15 (P=0.047) and Topo1 (P=0.002) were significantly higher. Based on those genes, a three-gene signature were established, which was calculated as follows: Index =0.488 - 0.020× expression level of APTX + 0.015× expression level of Topo1 - 0.011 × expression level of BRCA1. The three-gene signature was significantly associated with irinotecan sensitivity (rho=0.71, P<0.001). The sensitivity and specificity for the prediction of irinotecan sensitivity based on the three-gene signature reached 73% and 86%, respectively. In another independent testing set, the irinotecan inhibition rates in gastric samples with sensitive-signature were much higher than those with resistant-signature (65% vs. 22%, P<0.001). Irinotecan therapy with 20 mg/kg per week to immunodeficient mice carrying xenografts with sensitive-signature dramatically arrested the growth of tumors (P<0.001), but had no effect on mice carrying xenografts with resistant-signature.
  
  
  CONCLUSIONS
  The three-gene signature established herein is a potential predictive biomarker for irinotecan sensitivity in gastric cancer.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Jia
authors.initials: J
authors.lastname: Wei
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Guofeng
authors.initials: G
authors.lastname: Yue
authors.forename: Lixia
authors.initials: L
authors.lastname: Yu
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Li
authors.initials: L
authors.lastname: Xie
authors.forename: Zhengyun
authors.initials: Z
authors.lastname: Zou
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Qian
authors.forename: Yitao
authors.initials: Y
authors.lastname: Ding
authors.forename: Wenxian
authors.initials: W
authors.lastname: Guan
authors.forename: Baorui
authors.initials: B
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008875:Middle Aged; D008957:Models, Genetic; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D013429:Sulfatases; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D000077146:Irinotecan; D015238:Sulfotransferases; C470792:SULF2 protein, human; D013429:Sulfatases; D002166:Camptothecin