Functional analysis reveals that RBM10 mutations contribute to lung adenocarcinoma pathogenesis by deregulating splicing

• DOI: 10.1038/srep40488
• Publication Date: 2017-01-16T11:32:42Z
• Authors: Jiawei Zhao; Yue Sun; Yin Huang; Fan Song; Zengshu Huang; Yufang Bao; Ji Zuo; David Saffen; Zhen Shao; Wen Liu; Yongbo Wang
• Keywords: 0301 basic medicine; Lung Neoplasms; RNA Splicing; DNA Mutational Analysis; Mutation, Missense; RNA-Binding Proteins; Adenocarcinoma of Lung; Oncogenes; Adenocarcinoma; Survival Analysis; Article; 3. Good health; Gene Expression Regulation, Neoplastic; Alternative Splicing; 03 medical and health sciences; HEK293 Cells; Mutation; Humans; RNA, Messenger; Cell Proliferation

AbstractRBM10 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.