title: Differential regulation and synthetic lethality of exclusive RB1 and CDKN2A mutations in lung cancer.
abstract: Genetic alterations in lung cancer are distinctly represented in non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC). Mutation of the RB1 and CDKN2A genes, which are tightly associated with cell cycle regulation, is exclusive to SCLC and NSCLC cells, respectively. Through the systematic analysis of transcriptome and proteome datasets for 318 cancer cell lines, we characterized differential gene expression and protein regulation in RB1-mutant SCLC and CDKN2A-mutant NSCLC. Many of the genes and proteins associated with RB1-mutant SCLC cell lines belong to functional categories of gene expression and transcription, whereas those associated with CDKN2A-mutant NSCLC cell lines were enriched in gene sets of the extracellular matrix and focal adhesion. These results indicate that the loss of RB1 and CDKN2A function induces distinctively different signaling cascades in SCLC and NSCLC cells. In addition, knockdown of the RB1 gene in CKDN2A-mutant cell lines (and vice versa) synergistically inhibits cancer cell proliferation. The present study on the exclusive role of RB1 and CDKN2A mutations in lung cancer subtypes demonstrates a synthetic lethal strategy for cancer regulation.
authors.affiliation: Center for Advanced Bioinformatics and Systems Medicine, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Kim
authors.affiliation: Center for Advanced Bioinformatics and Systems Medicine, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Mee
authors.initials: M
authors.lastname: Song
authors.affiliation: Center for Advanced Bioinformatics and Systems Medicine, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Somin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Life Systems, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Yujeong
authors.initials: Y
authors.lastname: Seo
authors.affiliation: Department of Life Systems, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Yonghwan
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Center for Advanced Bioinformatics and Systems Medicine, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Sukjoon
authors.initials: S
authors.lastname: Yoon
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D020543:Proteome / Q000235:genetics; D016160:Retinoblastoma Protein / Q000096:biosynthesis* / Q000235:genetics; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000473:pathology; D059467:Transcriptome / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D020543:Proteome; D016160:Retinoblastoma Protein