title: CSNK1E/CTNNB1 are synthetic lethal to TP53 in colorectal cancer and are markers for prognosis.
abstract: Two genes are called synthetic lethal (SL) if their simultaneous mutations lead to cell death, but each individual mutation does not. Targeting SL partners of mutated cancer genes can kill cancer cells specifically, but leave normal cells intact. We present an integrated approach to uncovering SL pairs in colorectal cancer (CRC). Screening verified SL pairs using microarray gene expression data of cancerous and normal tissues, we first identified potential functionally relevant (simultaneously differentially expressed) gene pairs. From the top-ranked pairs, ~20 genes were chosen for immunohistochemistry (IHC) staining in 171 CRC patients. To find novel SL pairs, all 169 combined pairs from the individual IHC were synergistically correlated to five clinicopathological features, e.g. overall survival. Of the 11 predicted SL pairs, MSH2-POLB and CSNK1E-MYC were consistent with literature, and we validated the top two pairs, CSNK1E-TP53 and CTNNB1-TP53 using RNAi knockdown and small molecule inhibitors of CSNK1E in isogenic HCT-116 and RKO cells. Furthermore, synthetic lethality of CSNK1E and TP53 was verified in mouse model. Importantly, multivariate analysis revealed that CSNK1E-P53, CTNNB1-P53, MSH2-RB1, and BRCA1-WNT5A were independent prognosis markers from stage, with CSNK1E-P53 applicable to early-stage and the remaining three throughout all stages. Our findings suggest that CSNK1E is a promising target for TP53-mutant CRC patients which constitute ~40% to 50% of patients, while to date safety regarding inhibition of TP53 is controversial. Thus the integrated approach is useful in finding novel SL pairs for cancer therapeutics, and it is readily accessible and applicable to other cancers.
authors.affiliation: Bioinformatics Program, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan, R.O.C.; Institute of Biomedical Informatics, National Yang-Ming University, Taipei 112, Taiwan, R.O.C.
authors.forename: Khong-Loon
authors.initials: KL
authors.lastname: Tiong
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei 115, Taiwan, R.O.C.
authors.forename: Kuo-Ching
authors.initials: KC
authors.lastname: Chang
authors.affiliation: Department of Pathology, Changhua Christian Hospital, Changhua 505, Taiwan, R.O.C.; Department of Pathology, School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan, R.O.C.
authors.forename: Kun-Tu
authors.initials: KT
authors.lastname: Yeh
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Ting-Yuan
authors.initials: TY
authors.lastname: Liu
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei 115, Taiwan, R.O.C.
authors.forename: Jia-Hong
authors.initials: JH
authors.lastname: Wu
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei 115, Taiwan, R.O.C.
authors.forename: Ping-Heng
authors.initials: PH
authors.lastname: Hsieh
authors.affiliation: Department of Pathology, Changhua Christian Hospital, Changhua 505, Taiwan, R.O.C.; Jen-Teh Junior College of Medicine, Nursing Management, Miaoli 356, Taiwan, R.O.C.
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Lin
authors.affiliation: Molecular Medicine Program, Taiwan International Graduate Program, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, R.O.C.; Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei 112, Taiwan, R.O.C.
authors.forename: Wei-Yun
authors.initials: WY
authors.lastname: Lai
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei 115, Taiwan, R.O.C.
authors.forename: Yu-Chin
authors.initials: YC
authors.lastname: Hsu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, R.O.C.
authors.forename: Jeou-Yuan
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Department of Laboratory Medicine, and Center of RNA Biology and Clinical Application, China Medical University Hospital, China Medical University, Taichung 404, Taiwan, R.O.C.. Electronic address: d6781@mail.cmuh.org.tw.
authors.forename: Jan-Gowth
authors.initials: JG
authors.lastname: Chang
authors.affiliation: Bioinformatics Program, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan, R.O.C.; Institute of Statistical Science, Academia Sinica, Taipei 115, Taiwan, R.O.C.. Electronic address: gshieh@stat.sinica.edu.tw.
authors.forename: Grace S
authors.initials: GS
authors.lastname: Shieh
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D048149:Casein Kinase 1 epsilon / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D060888:Real-Time Polymerase Chain Reaction; D046888:Tissue Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D048149:Casein Kinase 1 epsilon