title: High-throughput RNAi screening of human kinases identifies predictors of clinical outcome in colorectal cancer patients treated with oxaliplatin.
abstract: The purpose of this study is to identify protein kinase genes that modulate oxaliplatin cytotoxicity in vitro and evaluate the roles of these genes in predicting clinical outcomes in CRC patients receiving oxaliplatin-based adjuvant chemotherapy. A high-throughput RNAi screening targeting 626 human kinase genes was performed to identify kinase genes whose inhibition potentiates oxaliplatin sensitivity in CRC cells. The associations between copy numbers of the candidate genes and recurrence-free survival and overall survival were analyzed in 142 stage III CRC patients receiving first-line oxaliplatin-based adjuvant chemotherapy who were enrolled from two independent hospitals. HT-RNAi screening identified 40 kinase genes whose inhibition potentiated oxaliplatin cytotoxicity in DLD1 cells. The relative copy number (RCN) of MAP4K1 and CDKL4 were associated with increased risks of both recurrence and death. Moreover, significant genes-based risk score and the ratios of RCN of different genes can further categorize patients into subgroups with distinctly differing outcomes. The estimated AUC for the prediction models including clinical variables plus kinase biomarkers was 0.77 for the recurrence and 0.82 for the survival models. The copy numbers of MAP4K1 and CDKL4 can predict clinical outcomes in CRC patients treated with oxaliplatin-based chemotherapy.
authors.affiliation: Center for Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.|Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Moubin
authors.initials: M
authors.lastname: Lin
authors.affiliation: Department of General Surgery, RuiJin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, RuiJin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Ajian
authors.initials: A
authors.lastname: Li
authors.affiliation: Center for Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Erjiang
authors.initials: E
authors.lastname: Tang
authors.affiliation: Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Wenxian
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Pathology, The Tenth People's Hospital Affiliated to Shanghai Tongji University School of Medicine, Shanghai, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Yin
authors.affiliation: Center for Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Huaguang
authors.initials: H
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D008875:Middle Aged; D018739:Oncogene Proteins v-erbB / Q000235:genetics; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D018739:Oncogene Proteins v-erbB; D009944:Organoplatinum Compounds; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077150:Oxaliplatin; C102102:hematopoietic progenitor kinase 1; D017346:Protein Serine-Threonine Kinases
keywords: RNAi screening; chemotherapy; colorectal cancer; recurrence; survival