title: Validation of a multi-omics strategy for prioritizing personalized candidate driver genes
abstract: Significant heterogeneity between different tumors prevents the discovery of cancer driver genes, especially in a patient-specific manner. We previously prioritized five personalized candidate mutation-driver genes in a hyper-mutated hepatocellular carcinoma patient using a multi-omics strategy. However, the roles of the prioritized driver genes and patient-specific mutations in hepatocarcinogenesis are unclear. We investigated the impact of the tumor-mutated allele on structure-function relationship of the encoded protein and assessed both loss- and gain-of-function of these genes and mutations on hepatoma cell behaviors in vitro. The prioritized mutation-driver genes act as tumor suppressor genes and inhibit cell proliferation and migration. In addition, the loss-of-function effect of the patient-specific mutations promoted cell proliferation and migration. Of note, the HNF1A S247T mutation significantly reduced the HNF1A transcriptional activity for hepatocyte nuclear factor 4 alpha (HNF4A) but did not disrupt nuclear localization of HNF1A. The results provide evidence for supporting the validity of our proposed multi-omics strategy, which supplies a new avenue for prioritizing mutation-drivers towards personalized cancer therapy.
authors.affiliation: Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010 P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Liang
authors.affiliation: Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010 P.R. China.
authors.forename: Liting
authors.initials: L
authors.lastname: Song
authors.affiliation: Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010 P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010 P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Tian
authors.affiliation: Department of Medical Oncology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730 P.R. China.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Proteomics, National Protein Science Beijing Center, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, 102206 P.R. China.
authors.forename: Songfeng
authors.initials: S
authors.lastname: Wu
authors.affiliation: Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010 P.R. China.
authors.forename: Wenxun
authors.initials: W
authors.lastname: Huang
authors.affiliation: Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010 P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Ren
authors.affiliation: Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010 P.R. China.
authors.forename: Ni
authors.initials: N
authors.lastname: Tang
authors.affiliation: Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010 P.R. China.
authors.forename: Keyue
authors.initials: K
authors.lastname: Ding
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009154:Mutation; D057285:Precision Medicine; D014162:Transfection
chemical_list: C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein
keywords: in vitro experiment; multi-omics; personalized mutation-driver genes; structure-function relationship; validation