title: Functional analysis reveals that RBM10 mutations contribute to lung adenocarcinoma pathogenesis by deregulating splicing.
abstract: RBM10 is an RNA splicing regulator that is frequently mutated in lung adenocarcinoma (LUAD) and has recently been proposed to be a cancer gene. How RBM10 mutations observed in LUAD affect its normal functions, however, remains largely unknown. Here integrative analysis of RBM10 mutation and RNA expression data revealed that LUAD-associated RBM10 mutations exhibit a mutational spectrum similar to that of tumor suppressor genes. In addition, this analysis showed that RBM10 mutations identified in LUAD patients lacking canonical oncogenes are associated with significantly reduced RBM10 expression. To systematically investigate RBM10 mutations, we developed an experimental pipeline for elucidating their functional effects. Among six representative LUAD-associated RBM10 mutations, one nonsense and one frameshift mutation caused loss-of-function as expected, whereas four missense mutations differentially affected RBM10-mediated splicing. Importantly, changes in proliferation rates of LUAD-derived cells caused by these RBM10 missense mutants correlated with alterations in RNA splicing of RBM10 target genes. Together, our data implies that RBM10 mutations contribute to LUAD pathogenesis, at least in large part, by deregulating splicing. The methods described in this study should be useful for analyzing mutations in additional cancer-associated RNA splicing regulators.
authors.affiliation: Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Zhao
authors.affiliation: School of Life Sciences, Fudan University, Shanghai, 200438, China.|Institutes of Brain Science, Fudan University, Shanghai, 200032, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Song
authors.affiliation: Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Zengshu
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
authors.forename: Yufang
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Zuo
authors.affiliation: Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.|Institutes of Brain Science, Fudan University, Shanghai, 200032, China.|State Key Laboratory for Medical Neurobiology, Fudan University, Shanghai, 200032, China.
authors.forename: David
authors.initials: D
authors.lastname: Saffen
authors.affiliation: Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D017398:Alternative Splicing / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004252:DNA Mutational Analysis; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009857:Oncogenes; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: C512260:RBM10 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins